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Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes.

To identify toxicity pathways a Oxidative stress is known to play important roles in nanomaterial-induced toxicities. However, the proteins and signaling pathways associated with nanomaterial-mediated oxidative stress and toxicity are largely unknown. To identify oxidative stress-responding toxicity pathways an Oxidative stress is known to play important roles in engineered nanomaterial induced cellular toxicity. However, the proteins and signaling pathways associated with the engineered nanomaterial mediated oxidative stress and toxicity are largely unknown.

To identify these toxicity Malignant human cell transformation of Marcellus Shale gas drilling flow back water. The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids.

To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The BEAS - 2 B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS - 2 B cells after long-term treatment.

BEAS - 2 B cells treated for 6 weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS - 2 B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining.

Hexavalent chromium [Cr VI ] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr VI -induced carcinogenesis remain unclear. MicroRNA miR is a key regulator of oncogenic processes. Studies have shown that miR exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 PDCD4.

Lung is a major target for arsenic carcinogenesis in humans. Identification of gene biomarkers for respiratory synctial virus infection in a bronchical epithelial cell line. Abstract: Respiratory syncytial virus RSV infection involves complex virus-host interplay. Thus, understanding how PM2. In the current study, we found that exposing human bronchial epithelial cells immortalized Beas - 2 B cells and primary cells to PM2. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 tumor protein p53 activation and the expression of its downstream target DRAM1 DNA damage regulated autophagy modulator 1 for the induction of autophagy.

These results thus extend the role of TPDRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial. Genotoxicity of short single-wall and multi-wall carbon nanotubes in human bronchial epithelial and mesothelial cells in vitro.

Although some types of carbon nanotubes CNTs have been described to induce mesothelioma in rodents and genotoxic effects in various cell systems, there are few previous studies on the genotoxicity of CNTs in mesothelial cells. The CNTs did not affect the level of. SATB2 expression increased anchorage-independent growth and cell migration in human bronchial epithelial cells.

The special AT-rich sequence-binding protein 2 SATB2 is a protein that binds to the nuclear matrix attachment region of the cell and regulates gene expression by altering chromatin structure. In our previous study, we reported that SATB2 gene expression was induced in human bronchial epithelial BEAS - 2 B cells transformed by arsenic, chromium, nickel and vanadium.

Fixed cells were then stained with propidium iodine PI and cell cycle phase was determined by fluorescent image cytometry. This work was a collaborative summer student project. The st. Cellular cytotoxic response induced by highly purified multi-wall carbon nanotube in human lung cells. Carbon nanotubes, a promising nanomaterial with unique characteristics, have applications in a variety of fields.

The cytotoxic effects of carbon nanotubes are partially due to the induction of oxidative stress; however, the detailed mechanisms of nanotube cytotoxicity and their interaction with cells remain unclear. In this study, the authors focus on the acute toxicity of vapor-grown carbon fiber, HTT, which is one of the most highly purified multi-wall carbon nanotubes MWCNT by high-temperature thermal treatment.

The authors exposed human bronchial epithelial cells BEAS - 2 B to HTT and measured the cellular uptake, mitochondrial function, cellular LDH release, apoptotic signaling, reactive oxygen species ROS generation and pro-inflammatory cytokine release. The HTT exposed cells showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. However, the exposed cells showed no obvious intracellular ROS generation.

Toxicological effects of polycyclic aromatic hydrocarbons and their derivatives on respiratory cells. Polycyclic aromatic hydrocarbons PAHs are found in ambient aerosols and particulate matter. Experimental studies have shown that PAHs and related chemicals can induce toxicological effects.

The present study aimed to investigate the effects of PAHs and their derivatives on the respiratory and immune systems and the underlying mechanisms. The human bronchial epithelial cell line BEAS - 2 B was exposed to PAHs and their derivatives, and the cytotoxicity and proinflammatory protein expression were then investigated.

Pyrene showed a weak cytotoxic effect. On the other hand, naphthalene and phenanthrene showed no significant effects. The increase was partly suppressed by protein kinase inhibitors such as the epidermal growth factor receptor-selective tyrosine kinase inhibitor and nuclear receptor antagonists such as the thyroid hormone receptor antagonist. The present study suggests that the toxicological effects of chemicals may be related to the different activities resulting from their structures, such as numbers of benzene rings and functional groups.

Furthermore, the chemical-induced increase in proinflammatory protein expression in bronchial epithelial cells was possibly a result of the activation of protein kinase pathways and nuclear receptors. The increase may partly contribute to the adverse health effects of atmospheric PAHs.

Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment. Airway dendritic cells DCs are crucial for allergen-induced sensitization and inflammation in allergic asthma. After allergen challenge, an increased number of DCs is observed in airway epithelium from patients with allergy. Because Der p 1, a cysteine protease allergen from Dermatophagoides pteronyssinus , induces chemokine production by bronchial epithelial cells BECs , the purpose of this investigation was to evaluate the capacity of BEC exposed to Der p 1 to recruit DCs.

In a reconstituted polarized epithelium, apical application of Der p 1 enhanced MDDC precursor migration into the epithelial layer. No migration of immature and mature DCs was observed. These data confirmed that BECs participate in the homeostasis of the DC network present within the bronchial epithelium through the secretion of chemokines. In allergic asthma, upregulation of CCL20 production induced LC recruitment, the role of which remains to be determined.

Gerloff, Janice; Sundar, Isaac K. Abstract Recent studies suggest that electronic cigarette e-cig flavors can be harmful to lung tissue by imposing oxidative stress and inflammatory responses. The potential inflammatory response by lung epithelial cells and fibroblasts exposed to e-cig flavoring chemicals in addition to other risk-anticipated flavor enhancers inhaled by e-cig users is not known. The goal of this study was to evaluate the release of the proinflammatory cytokine interleukin-8 [IL-8] and epithelial barrier function in response to different e-cig flavoring chemicals identified in various e-cig e-liquid flavorings and vapors by chemical characterization using gas chromatography—mass spectrometry analysis.

Human bronchial epithelial cells Beas 2 B , human mucoepidermoid carcinoma epithelial cells H , and human lung fibroblasts HFL-1 were treated with each flavoring chemical for 24 hours. Acetoin and diacetyl treatment induced IL-8 release in Beas 2 B cells. Flavorings, such as ortho-vanillin and maltol, induced IL-8 release in Beas 2 B cells , but not in H cells.

Flavoring chemicals rapidly impaired epithelial barrier function in human bronchial epithelial cells HBE as measured by electric cell. Recent studies suggest that electronic cigarette e-cig flavors can be harmful to lung tissue by imposing oxidative stress and inflammatory responses. The goal of this study was to evaluate the release of the proinflammatory cytokine interleukin-8 [IL-8] and epithelial barrier function in response to different e-cig flavoring chemicals identified in various e-cig e-liquid flavorings and vapors by chemical characterization using gas chromatography-mass spectrometry analysis.

Flavoring chemicals rapidly impaired epithelial barrier function in human bronchial epithelial cells HBE as measured by electric cell surface. Long term exposure to environmental concentrations of diesel exhaust particles does not impact the phenotype of human bronchial epithelial cells. Chronic exposure to diesel engine exhausts is associated with an increased risk of pulmonary diseases including lung cancer.

Diesel engine exhausts contain large amounts of diesel exhaust particles DEP on which are adsorbed several carcinogenic compounds such as polycyclic aromatic hydrocarbons. Acute toxicity of high concentrations of DEP has been largely demonstrated in various in vitro cellular models. In contrast, the cellular and molecular impacts of low environmental concentrations of DEP on the phenotype of chronically exposed lung epithelial cells remain to be investigated.

However, chronic exposure to DEP did not change cell morphology, trigger epithelial-mesenchymal transition or increase anchorage-independent cell growth. Our results thus demonstrate that the chronic exposure to low DEP concentrations could increase cytochrome PA gene expression in BEAS - 2 B cells but did not induce molecular effects related to genotoxicity, oxidative stress or inflammation. Malignant human cell transformation of Marcellus shale gas drilling flow back water.

The produced flow back waters after hydraulic stimulation is known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these waste waters, flow back water from five Marcellus hydraulic fracturing oil and gas wells were analyzed.

A cytotoxicity study using colony formation as the endpoint was carried out to define the LC50 values of test samples using human bronchial epithelial cells BEAS - 2 B. Barium and strontium were among the most abundant metals in these samples and the same metals were found elevated in BEAS - 2 B cells after long-term treatment.

BEAS - 2 B cells treated for 6 weeks with flow back waters produced colony formation in soft agar that was concentration dependant. In addition, flow back water-transformed BEAS - 2 B cells show a better migration capability when compared to control cells. BEAS - 2 B cells treated for 6weeks with flow back waters produced colony formation in soft agar that was concentration dependent. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

Stueckle, Todd A. Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS - 2 B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed B-As cells. Following a six month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines.

Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis IPA to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS - 2 B cells.

B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction.

Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment.

Lung fibroblasts may play an important role in clearing apoptotic bodies of bronchial epithelial cells generated by exposure to PHMG-P-containing solution. Polyhexamethylene guanidine PHMG has been widely used in the industry owing to its excellent biocidal, anti-corrosive, and anti-biofouling properties.

However, no appropriate treatment has yet been found because the detail toxic mechanism has not been identified. Based on these results, we suggest that pulmonary exposure to PHMG-P induces apoptosis of bronchial epithelial cells and lung fibroblasts might play an important role in the clearance of the apoptotic debris.

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates. Inflammation and apoptosis are crucial mechanisms for the development of the acute respiratory distress syndrome ARDS. Currently, there is no specific pharmacological therapy for ARDS. We have evaluated the ability of a new family of 1,2,3,5-tetrasubstituted pyrrol compounds for attenuating lipopolysaccharide LPS -induced inflammation and apoptosis in an in vitro LPS-induced airway epithelial cell injury model based on the first steps of the development of sepsis-induced ARDS.

Rhein and emodin, two representative compounds with proven activity against the effects of LPS, were used as reference compounds. The pyrrol compound that was termed DTA had the strongest inhibitory activity and was selected as the lead compound to further explore its properties. The observed antiapoptotic effect of DTA was associated with the upregulation of antiapoptotic Bcl-2 and downregulation of proapoptotic Bax and active caspase-3 protein levels.

Our findings demonstrate the potent anti-inflammatory and antiapoptotic properties of the pyrrol DTA compound and suggest that it could be considered as a potential drug therapy for the acute phase of sepsis and septic ARDS. Further investigations are needed to examine and validate these mechanisms and effects in a clinically relevant animal model of sepsis and sepsis-induced ARDS. Comparison between ultrafine and fine particulate matter collected in Lebanon: Chemical characterization, in vitro cytotoxic effects and metabolizing enzymes gene expression in human bronchial epithelial cells.

During the last few years, the induction of toxicological mechanisms by atmospheric ultrafine particles UFP has become one of the most studied topics in toxicology and a subject of huge debates. Fine particles FP and UFP collected at urban and rural sites in Lebanon were studied for their chemical composition and toxicological effects.

UFP were found more enriched in trace elements, secondary inorganic ions, total carbon and organic compounds than FP. Our findings showed that UFP caused earlier alterations of mitochondrial metabolism and membrane integrity from the lowest concentrations.

Gene expression profiling of the effects of organic dust in lung epithelial and THP-1 cells reveals inductive effects on inflammatory and immune response genes. The intensification and concentration of animal production operations expose workers to high levels of organic dusts in the work environment.

Exposure to organic dusts is a risk factor for the development of acute and chronic respiratory symptoms and diseases. Lung epithelium plays important roles in the control of immune and inflammatory responses to environmental agents to maintain lung health. To better understand the effects of organic dust on lung inflammatory responses, we characterized the gene expression profiles of A alveolar and Beas 2 B bronchial epithelial and THP-1 monocytic cells influenced by exposure to poultry dust extract by DNA microarray analysis using Illumina Human HT v4 Expression BeadChip.

We found that A alveolar and Beas 2 B bronchial epithelial and THP-1 cells responded with unique changes in the gene expression profiles with regulation of genes encoding inflammatory cytokines, chemokines, and other inflammatory proteins being common to all the three cells. Pathway analysis indicated that dust extract induced changes in gene expression influenced functions related to cellular growth and proliferation, cell death and survival, and cellular development.

These data show that a broad range of inflammatory mediators produced in response to poultry dust exposure can modulate lung immune and inflammatory responses. This is the first report on organic dust induced changes in expression profiles in lung epithelial and THP-1 monocytic cells. Secondary organic aerosol SOA derived from the photochemical oxidation of isoprene contributes a substantial mass fraction to atmospheric fine particulate matter PM 2.

The formation of isoprene SOA is influenced largely by anthropogenic emissions through multiphase chemistry of its multigenerational oxidation products. Considering the abundance of isoprene SOA in the troposphere, understanding mechanisms of adverse health effects through inhalation exposure is critical to mitigating its potential impact on public health. In this study, we assessed the effects of isoprene SOA on gene expression in human airway epithelial cells BEAS - 2 B through an air-liquid interface exposure.

Gene expression profiling of 84 oxidative stress and inflammation-associated human genes was performed. Our results show that the expression levels of 29 genes were significantly altered upon isoprene SOA exposure under noncytotoxic conditions p cell line.

Together with detailed characterization of SOA constituents, this study reveals the impact of isoprene SOA exposure on lung responses and highlights the importance of further understanding its potential health outcomes. Hexavalent chromium Cr VI promotes lung injury and pulmonary diseases through poorly defined mechanisms that may involve the silencing of inducible protective genes.

The current study investigated the hypothesis that Cr VI actively signals through a signal transducer and activator of transcription 1 STAT1 —dependent pathway to silence nickel Ni —induced expression of vascular endothelial cell growth factor A VEGFA , an important mediator of lung injury and repair.

This study demonstrates that metal-stimulated signaling cascades interact to regulate transcription and induction of adaptive or repair responses in airway cells. Hexavalent chromium [Cr VI ] compounds e. Inhalation is a major route of exposure which directly exposes the bronchial epithelium.

Previous studies with non-cancerous human bronchial epithelial cells BEAS - 2 B demonstrated that Cr VI treatment results in the irreversible inhibition of thioredoxin reductase TrxR and the oxidation of thioredoxins Trx and peroxiredoxins Prx. Nitration of tyrosine residues of TrxR was not observed following Cr VI treatment, further ruling out peroxynitrite as a significant contributor to the irreversible inhibition of TrxR.

Overall, the redox stress that results from Cr VI exposure shows selectivity for key proteins which are known to be important for redox signaling, antioxidant defense, and cell survival. Effects of bile acids on human airway epithelial cells : implications for aerodigestive diseases. Gastro-oesophageal reflux and aspiration have been associated with chronic and end-stage lung disease and with allograft injury following lung transplantation.

This raises the possibility that bile acids may cause lung injury by damaging airway epithelium. The aim of this study was to investigate the effect of bile acid challenge using the immortalised human bronchial epithelial cell line BEAS - 2 B. A h challenge evaluated the effect of individual primary and secondary bile acids.

Lithocholic acid, deoxycholic acid, chenodeoxycholic acid and cholic acid were successfully used to stimulate cultured BEAS - 2 B cells at different concentrations. Aspiration of bile acids could potentially cause cell damage, cell death and inflammation in vivo. This is relevant to an integrated gastrointestinal and lung physiological paradigm of chronic lung disease, where reflux and aspiration are described in both chronic lung diseases and allograft injury.

Investigating mitochondrial dysfunction in human lung cells exposed to redox-active PM components. Exposure to ambient particulate matter PM causes cardiopulmonary morbidity and mortality through mechanisms that involve oxidative stress.

We previously reported that 1,2-NQ increases mitochondrial H 2 O 2 production through an unidentified mechanism. We sought to characterize the effects of 1,2-NQ exposure on mitochondrial respiration as a source of H 2 O 2 in human airway epithelial cells. We measured the effects of acute exposure to 1,2-NQ on oxygen consumption rate OCR in the human bronchial epithelial cell line BEAS - 2 B and mitochondrial preparations using extracellular flux analysis.

Complex-specific assays and NADPH depletion by glucose deprivation distinguished between mitochondrial and non-mitochondrial oxygen utilization. Similar effects were observed with the environmentally relevant redox-cycling quinones 1,4-naphthoquinone and 9,phenanthrenequinone, but not with quinones that do not redox cycle, such as 1,4-benzoquinone.

In mitochondrial preparations, 1,2-NQ caused a decrease in Complex I-linked substrate oxidation, suggesting impairment of pyruvate utilization or transport, a novel mechanism of mitochondrial inhibition by an environmental exposure. This study also highlights the methodological utility and challenges in the use of extracellular flux analysis to elucidate the mechanisms of action of redox-active electrophiles present in ambient air.

Published by Elsevier Inc. X-irradiation of human bronchial cancer cells causes the bystander effects in normal bronchial cells in vitro. Using X radiation commonly used in radiotherapy of cancers we investigated bystander interactions between human cells : irradiated A bronchial carcinoma human cells and non irradiated BEAS - 2 B normal bronchial epithelial cells. Non irradiated cells were incubated in medium transferred from irradiated A cells ICM-irradiation conditioned medium for 48h and next the chromosomal damage and apoptosis were estimated.

Conditioned medium collected from irradiated cancer cells induced in non irradiated cells of the same line as well as in BEAS - 2 B normal cells genetic changes such as micronuclei, chromatid and chromosomal breaks and condensation of chromatin characteristic for processes of apoptosis.

The presented results in this study could have implications for human radiation risk and in evaluating the secondary effects of radiotherapy. Highlights: Black-Right-Pointing-Pointer Hyperoxia induces apoptosis and chitinase 3-like 1 expression in human airway epithelial cells. Black-Right-Pointing-Pointer Presence of chitinase 3-like 1 affects airway epithelial cell death after hyperoxic exposure. Recently, the role of chitinase 3-like 1 CHI3L1 , a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models.

However, the role of CHI3L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CHI3L1 in this process are poorly understood. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy.

CHI3L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CHI3L1 overexpression promoted cell death after hyperoxia exposure. Pathway modeling of the protein differential expression showed that CuO NP affect proteins relevant in cellular function and maintenance, protein synthesis, cell death and survival, cell cycle and cell morphology.

Some of the signaling pathways represented by BEAS - 2 B proteins responsive to the NP included mTOR signaling, protein ubiquitination pathway, actin cytoskeleton signaling and epithelial adherens junction signaling. Follow-up experiments showed that CuO NP altered actin cytoskeleton, protein phosphorylation and protein ubiquitination level.

Gene expression analysis uncovers novel Hedgehog interacting protein HHIP effects in human bronchial epithelial cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences.

Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. BEAS - 2 B cells did not differentiate or develop tight junctions.

These data highlight the challenges in working with primary cell models and the need for careful characterisation and selection of systems to answer specific research questions. Toxicological responses of exhaust emissions of biodiesel are different due to variation in methods of generation and the tested biological models.

A cytotoxicity assay and cytokine secretion experiments were evaluated in human bronchial epithelial cells BEAS - 2 B. Cells were exposed to polar acetone and nonpolar hexane extracts from particles obtained from fuel exhaust: fossil diesel B5 , pure soybean biodiesel B , soybean biodiesel with additive BA and ethanol additive EtOH.

Biodiesel and its additives exhibited higher organic and inorganic constituents on particles when compared to B5. In fact quite the opposite, a cell proliferation effect induced by the B and BA extracts is reported. A small increase in concentrations of inflammatory mediators Interleukin-6, IL-6; and Interleukin-8, IL-8 in the medium of biodiesel-treated cells was observed, however, no statistical difference was found.

An interesting finding indicates that the presence of metals in the nonpolar hexane fraction of biodiesel fuel B represses cytokine release in lung cells. This was revealed by the use of the metal chelator. Biodiesel from soybean promotes cell proliferation in vitro. Results suggest that metals associated with biodiesel's organic constituents might play a significant role in molecular mechanisms associated to cellular proliferation and immune responses.

Published by Elsevier Ltd. Analysis of nicotine-induced DNA damage in cells of the human respiratory tract. Epithelium of the upper and lower airways is a common origin of tobacco-related cancer. The main tobacco alkaloid nicotine may be associated with tumor progression. The potential of nicotine in inducing DNA mutations as a step towards cancer initiation is still controversially discussed. Different subtypes of nicotinic acetylcholine receptors nAChR are expressed in human nasal mucosa and a human bronchial cell line representing respiratory mucosa as a possible target for receptor-mediated pathways.

In the present study, both cell systems were investigated with respect to DNA damage induced by nicotine and its mechanisms. Specimens of human nasal mucosa were harvested during surgery of the nasal air passage. After enzymatic digestion over night, single cells were exposed to an increasing nicotine concentration between 0. DNA damage was assessed using the alkali version of the comet assay.

Dose finding experiments for mecamylamine to evaluate the maximal inhibitory effect were performed in the human bronchial cell line BEAS - 2 B with an increasing mecamylamine concentration and a constant nicotine concentration. After 1h of nicotine exposure with 0.

Further co-incubation experiments with mecamylamine and NAC were performed using 1. The strongest inhibitory effect was measured at 1. Both, the antioxidant NAC at a concentration of 1. A nicotine-induced increase or decrease in. Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin. However, the exact role of Bit1 in regulating malignant growth and transformation of human lung epithelial cells , which are origin of most forms of human lung cancers, has not been examined.

To this end, we have downregulated the endogenous Bit1 expression in the immortalized non-tumorigenic human bronchial epithelial BEAS - 2 B cells. The loss of Bit1-induced transformed phenotypes was in part attributable to the repression of E-cadherin expression since forced exogenous E-cadherin expression attenuated the malignant phenotypes of the Bit1 knockdown cells. Importantly, we show that the loss of Bit1 expression in BEAS - 2 B cells resulted in increased Erk activation, which functions upstream to promote TLE1-mediated transcriptional repression of E-cadherin.

These collective findings indicate that loss of Bit1 expression contributes to the acquisition of malignant phenotype of human lung epithelial cells via Erk activation-induced suppression of E-cadherin expression. A particular challenge for nanotoxicology is the evaluation of the biological fate and toxicity of nanomaterials that dissolve in aqueous fluids. Zinc oxide nanomaterials are of particular concern because dissolution leads to release of the toxic divalent zinc ion.

Although dissolved zinc ions have been implicated in ZnO cytotoxicity, direct identification of the chemical form of zinc taken up by cells exposed to ZnO nanoparticles, and its intracellular fate, has not yet been achieved. We combined high resolution X-ray spectromicroscopy and high elemental sensitivity X-ray microprobe analyses to determine the fate of ZnO and less soluble iron-doped ZnO nanoparticles following exposure to cultures of human bronchial epithelial cells , BEAS - 2 B.

We complemented two-dimensional X-ray imaging methods with atomic force microscopy of cell surfaces to distinguish between nanoparticles that were transported inside the cells from those that adhered to the cell exterior. The data suggest cellular uptake of ZnO nanoparticles is a mechanism of zinc accumulation in cells. These results corroborate a model for ZnO nanoparticle toxicity that is based on nanoparticle uptake followed by intracellular dissolution.

Prediction of delivery of organic aerosols onto air-liquid interface cells in vitro using an electrostatic precipitator. To better characterize biological responses to atmospheric organic aerosols, the efficient delivery of aerosol to in vitro lung cells is necessary. To augment in vitro assessment using the ESP exposure device, the particle dose was predicted for various sampling parameters such as particle size, ESP deposition voltage, and sampling flowrate.

The dose model was evaluated against the experimental measured mass of collected airborne particles. The high flowrate used in this study increased aerosol dose but failed to achieve cell stability. The ESP device and the resulting model were applied to in vitro studies i. Abiotic stress of ambient cold temperature regulates the host receptivity to pathogens by cell surfaced sialic acids. Ambient cold temperature, as an abiotic stress, regulates the survival, stability, transmission, and infection of pathogens.

However, the effect of cold temperature on the host receptivity to the pathogens has not been fully studied. The expression of several sialyltransferases were also increased by exposure to cold temperature. On the other hand, the treatment of Lith-Gly, a sialyltransferase inhibitor, blocked the cold-induced expression of sialic acids on surface of BEAS - 2 B cells.

Lithospermum erythrorhizon extract inhibits Der p2-induced inflammatory response through alleviation of thymic stromal lymphopoietin, nuclear factor Kappa B, and inflammasome expression in human bronchial epithelial cells. Lithospermum erythrorhizon LE and Angelica sinensis AS , widely used in several folk medicine for wound, pus discharge and dermatitis for the history of several hundred years in Asian countries.

Sarker, Altaf H. Secondhand smoke SHS is a confirmed lung carcinogen that introduces thousands of toxic chemicals into the lungs. SHS contains chemicals that have been implicated in causing oxidative DNA damage in the airway epithelium. Although DNA repair is considered a key defensive mechanism against various environmental attacks, such as cigarette smoking, the associations of individual repair enzymes with susceptibility to lung cancer are largely unknown.

Representative SSS chemical compounds in the medium were analyzed by mass spectrometry. Taken together, our data strongly suggest that decreased repair of oxidative DNA base lesions due to an impaired NEIL2 expression in non-smokers exposed to SSS would lead to accumulation of mutations in genomic DNA of lung cells over time, thus contributing to the onset of SSS-induced lung cancer.

Cigarette smoke CS is a major risk of chronic obstructive pulmonary disease COPD , contributing to airway inflammation. Our previous study revealed that silymarin had an anti-inflammatory effect in CS- exposed mice. In this study, we attempt to further elucidate the molecular mechanisms of silymarin in CS extract CSE -induced inflammation using human bronchial epithelial cells.

We also observed that inhibiting the activity of ERK with specific inhibitor U led to reduced autophagic level, while knockdown of autophagic gene Beclin-1 and Atg5 decreased the levels of ERK and p38 phosphorylation. Silymarin could attenuate inflammatory responses through intervening in the crosstalk between autophagy and ERK MAPK pathway, and might be an ideal agent treating inflammatory pulmonary diseases.

China's Xuan Wei County in Yunnan Province have the world's highest incidence of lung cancer in nonsmoking women times higher than the rest of China. Previous studies showed, this high lung cancer incidence may be associated with the silica particles embedded in the production combustion from the C1 coal. The aim of this study is to separate the silica particles from production combustion from the C1 bituminous coal in Xuan Wei County of Yunnan Province, and study in vitro toxicity of naturally occurring silica particles on BEAS - 2 B.

Nanodiamond internalization in cells and the cell uptake mechanism. Perevedentseva, E. In this work, internalization of nm nanodiamonds by A lung human adenocarcinoma cell , Beas - 2 b non-tumorigenic human bronchial epithelial cell , and HFL-1 fibroblast-like human fetal lung cell is studied and compared. The penetration of nanodiamond into the cells was observed using confocal fluorescence imaging and Raman imaging methods. Visualization of the nanodiamond in cells allows comparison of the internalization for diamond nanoparticles in cancer A cell , non-cancer HFL-1, and Beas - 2 b cells.

The dose-dependent and time-dependent behavior of nanodiamond uptake is observed in both cancer as well as non-cancer cells. The mechanism of nanodiamond uptake by cancer and non-cancer cells is analyzed by blocking different pathways. The uptake of nanodiamond in both cancer and non-cancer cells was found predominantly via clathrin-dependent endocytosis.

In spite of observed similarity in the uptake mechanism for cancer and non-cancer cells , the nanodiamond uptake for cancer cell quantitatively exceeds the uptake for non-cancer cells , for the studied cell lines. The observed difference in internalization of nanodiamond by cancer and non-cancer cells is discussed. Poisson-event-based analysis of cell proliferation.

A protocol for the assessment of cell proliferation dynamics is presented. This is based on the measurement of cell division events and their subsequent analysis using Poisson probability statistics. Detailed analysis of proliferation dynamics in heterogeneous populations requires single cell resolution within a time series analysis and so is technically demanding to implement. Here, we show that by focusing on the events during which cells undergo division rather than directly on the cells themselves a simplified image acquisition and analysis protocol can be followed, which maintains single cell resolution and reports on the key metrics of cell proliferation.

The technique is demonstrated using a microscope with 1. Analysis of the statistics of the interevent times i. Grain dust induces IL-8 production from bronchial epithelial cells : effect on neutrophil recruitment. There have been several investigations suggesting an involvement of activated neutrophils in the development of grain dust GD -induced occupational asthma. Interleukin-8 in the sputa from GD-induced asthmatic patients increased significantly after the exposure to GD.

To confirm IL-8 production from bronchial epithelial cells when exposed to GD, and to evaluate the role of IL-8 on neutrophil recruitment. We cultured Beas - 2 B , a bronchial epithelial cell line. The level of released IL-8 in the supernatant was measured by enzyme-linked immunosorbent assay.

Neutrophil chemotactic activity of the culture supernatant was determined by modified Boyden chamber method. Interleukin-8 production and neutrophil chemotactic activity from bronchial epithelial cells significantly increased with additions of GD in a dose-dependent manner P cells may be a major cytokine, which induces neutrophil migration into the airways when exposed to GD. The molecular mechanisms of Cr VI carcinogenesis appear to be complex and are poorly defined.

We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr VI treatments in a dose- and time-dependent fashion in BEAS - 2 B lung epithelial cells. The inhibition also occurs in A lung bronchial carcinoma cells. Benzo[a]pyrene BaP , a well-known environmental carcinogen, promotes oxidative stress and DNA damage. Curcumin and vitamin E VE have potent antioxidative activity that protects cells from oxidative stress and cellular damage.

The objectives of the present study were to investigate the adverse effects of BaP on normal human lung epithelial cells BEAS - 2 B , the potential protective effects of curcumin and VE against BaP-induced cellular damage, and the molecular mechanisms of action. Moreover, the level of activated p53 and PARP-1 were significantly induced by BaP, whereas this induction was markedly reduced after curcumin and VE co-treatment. Survivin was significantly down-regulated by BaP, and curcumin significantly restored survivin expression in BaP- exposed cells.

Curcumin and VE could reverse some of these BaP-mediated alterations and therefore be effective natural compounds against the adverse effects of BaP in lung cells. Plasmacytoid dendritic cells pDCs belong to the family of dendritic cells and possess specific features that distinguish them from conventional dendritic cells.

For instance, pDC are the main interferon-alpha-secreting cells. Plasmacytoid dendritic cells exert both proinflammatory and regulatory functions. This is attested by the involvement of pDC through interferon-alpha secretion in several autoimmune diseases, and by the implication of pDC in tolerance.

Here, we discuss the factors that may influence this polarization. Arsenic exposure induces the Warburg effect in cultured human cells. Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis. A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases.

Following an initial observation that arsenite- exposed cells in culture acidify their media more rapidly than control cells , the report here shows that low level exposure to arsenite 75 ppb is sufficient to induce aerobic glycolysis the Warburg effect as a generalized phenomenon in cultured human primary cells and cell lines.

Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1A. Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases.

Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD increased liver tumors and promoted lung metaplasia in females. We recently reported that depletion of this protein promotes lung epithelial cell transformation induced by hexavalent chromium [Cr VI ]. However, the early molecular events that mediate this process are not clear.

Our data reveal 83 differentially expressed genes. Up-regulation of some neuro-specific genes is also evident, particularly ubiquitin carboxyl-terminal hydrolase L1 UCHL1 , a deubiquitinase and potential biomarker for lung cancer. Gene 33 deletion also significantly reduced cell proliferation. Interestingly, Cr VI exposure eliminated the difference in cell proliferation between the two genotypes.

Gene 33 deletion also significantly elevated cell migration. Our data indicate that combined Gene 33 deletion and chronic Cr VI exposure produces a gene expression pattern and a phenotype resemble those of the transformed lung epithelial cells. Given the known association of UCHL1 with lung cancer, we propose that UCHL1 is an important player in the early stage of lung epithelial cell transformation and tumorigenesis.

The efficiency of photovoltaic cells exposed to pulsed laser light. Future space missions may use laser power beaming systems with a free electron laser FEL to transmit light to a photovoltaic array receiver. The induction pulse format was simulated with an watt average power copper vapor laser and the RF format with a frequency-doubled mode-locked Nd:YAG laser.

Averaged current vs bias voltage measurements for each cell were taken at various optical power levels and the efficiency measured at the maximum power point. Experimental results show that the conversion efficiency for the cells tested is highly dependent on cell minority carrier lifetime, the width and frequency of the pulses, load impedance, and the average incident power.

Three main effects were found to decrease the efficiency of solar cells exposed to simulated FEL illumination: cell series resistance, LC 'ringing', and output inductance. Improvements in efficiency were achieved by modifying the frequency response of the cell to match the spectral energy content of the laser pulse with external passive components.

Xianyu decoction attenuates the inflammatory response of human lung bronchial epithelial cell. Xianyu decoction XD , a Chinese experience recipe, shows inhibitory effects on lung cancer. However, the potential functions of XD on pneumonia were unknown. This study aimed to investigate the effect of XD on inflammatory response of childhood pneumonia.

High expression of miRa was observed in serum and cell model of pneumonia. XD treatment downregulated the level of miRa in pneumonia children. XD downregulated the level of miRa in serum of pneumonia children. Suppressive effects of formoterol and salmeterol on eotaxin-1 in bronchial epithelial cells. Eotaxin-1 CCL11 , an eosinophil-specific C-C chemokine, is a potent chemoattractant for mobilization of eosinophils into airways after allergic stimulation.

Eotaxin-1 recruits eosinophils into inflammatory sites, and may play a role in the pathogenesis of asthma. Formoterol and salmeterol are two inhaled long acting beta 2 adrenoceptor agonists LABAs , widely used for the local treatment of asthma. However, little is known about their effects on the eotaxin-1 expression of bronchial epithelial cells. Effects of formoterol and salmeterol on nuclear and cytosolic pSTAT-6 expression were evaluated by Western blot and immunofluorescence study.

A specific beta 2 adrenoceptor antagonist ICI , reversed their suppression of eotaxin-1 production. Forskolin, an cAMP activator, could also suppress the expression of eotaxin-1 by IL-4 in a dose dependent manner 10 -7 m. The western blot and immunofluorescence studies demonstrated that formoterol 10 -7 m suppressed the nuclear expression of pSTAT Formoterol and salmeterol, two inhaled long-acting beta 2 agonists, down-regulated IL induced eotaxin-1 expression in BEAS - 2 B cells.

The effect was mediated via the beta 2 adrenoceptor, and cAMP. Formoterol significantly down-regulated pSTAT6 at higher concentration, and further turned off the IL-4 signaling pathway. Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells following exposure to silver nitrate. Silver Ag possesses antibacterial activity and has been used in wound dressings and deodorant powders worldwide.

However, the metabolic behavior and biological roles of Ag in mammals have not been well characterized. In the present study, we exposed human bronchial epithelial cells BEAS - 2 B to AgNO3 and investigated uptake and intracellular distribution of Ag, expression of metallothionein MT , generation of reactive oxygen species ROS , and changes in mitochondrial respiration. The culture medium concentration of Ag decreased with time and stabilized at 12h. The concentration of both Ag and MT in the soluble cellular fraction increased up to 3h and then decreased, indicating that cytosolic Ag relocated to the insoluble fraction of the cells.

The intensity of fluorescence derived from ROS was elevated in the mitochondrial region at 24h. Ag decreased mitochondrial oxygen consumption in a dose-dependent manner and the activity of mitochondrial complex I-IV enzymes was significantly inhibited following exposure to Ag. In a separate experiment, we found that hydrogen peroxide H2O2 at concentrations as low as 0. These results suggest MT was decomposed by cytosolic H2O2, and then Ag released from MT relocated to insoluble cellular fractions and inhibited electron chain transfer of mitochondrial complexes, which eventually led to cell damage.

Malondialdehyde-acetaldehyde MAA adducted proteins bind to scavenger receptor A in airway epithelial cells. Co-exposure to cigarette smoke and ethanol generates malondialdehyde and acetaldehyde, which can subsequently lead to the formation of aldehyde-adducted proteins. We have previously shown that exposure of bronchial epithelial cells to malondialdehyde-acetaldehyde MAA adducted protein increases protein kinase C PKC activity and proinflammatory cytokine release.

A specific ligand to scavenger receptor A SRA , fucoidan, blocks this effect. Specific cell surface membrane dye co-localized with upregulated SRA after exposure to MAA for min and subsided by 20 min. These data demonstrate that aldehyde-adducted proteins in the lungs rapidly bind to SRA and internalize this receptor prior to the MAA-adducted protein stimulation of PKC-dependent inflammatory cytokine release in airway epithelium.

Berger, John P. Specific cell surface membrane dye co-localized with upregulated SRA after exposure to MAA for 3—7 min and subsided by 20 min. Overexpression of HO-1 assisted PM2. During these episodes, a surge in hospital visits for acute respiratory symptoms and respiratory diseases exacerbation has been reported to be associated with acute exposure to high-levels of particulate matters.

To investigate cell fate determination and the underlying pathogenic mechanisms during severe haze episodes or smog events, we exposed human lung epithelial cells BEAS - 2 B to PM2. Exposure to PM2. In contrast to necrosis, PM2. In conclusion, our results demonstrate that acute exposure to high PM2. Further, this study reveals dual roles for HO-1 in PM2. Sodium metavanadate exhibits carcinogenic tendencies in vitro in immortalized human bronchial epithelial cells.

Pentavalent vanadium compounds induce intracellular changes in vitro that are consistent with those of other carcinogenic substances. While there is no clear evidence that vanadium compounds cause cancer in humans, vanadium pentoxide causes lung cancer in rodents after long-term inhalation exposures and in turn IARC has categorized it as a group 2B possible human carcinogen. The goal of this study was to investigate the carcinogenicity of NaVO3 in the human immortalized bronchial epithelial cell line, Beas - 2 B.

A dose-dependent increase in the number of colonies was observed. In scratch tests, NaVO3-transformed clones could repair a wound faster than controls. DEG from this experiment were compared with the DEG of 5 week NaVO3 exposure with or without recovery, all with adjusted p-values cells , and the recovered cells. Although all-trans retinoic acid ATRA is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment.

Therefore, the development of new drugs or effective combination therapy is urgently needed. This treatment also induced growth arrest at the G1 phase. Driver or passenger effects of augmented c-Myc and Cdc20 in gliomagenesis. Cdc20 and c-Myc are commonly overexpressed in a broad spectrum of cancers, including glioblastoma GBM. Despite this clear association, whether c-Myc and Cdc20 overexpression is a driver or passenger event in gliomagenesis remains unclear.

Both c-Myc and Cdc20 induced the proliferation of primary glial progenitor cells. In contrast, Cdc20 decreased the GBM incidence from We used glial progenitor cells from Ntv-a newborn mice to evaluate the role of c-Myc and Cdc20 in the proliferation and transformation of GBM in vitro and in vivo.

These results suggest that the driver or passenger of oncogene signaling is dependent on cellular status. Inhibition of cell differentiation of c-Myc may be a target for anti-glioma therapy. Romeo, Megan M. The human T-cell leukemia retrovirus type-1 HTLV-1 p30II protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation.

However, the molecular and biochemical events that mediate the cooperation between p30II and c-MYC remain to be completely understood. Moreover, p30II inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. Sequential treatment with aurora B inhibitors enhances cisplatin-mediated apoptosis via c-Myc. Platinum compound such as cisplatin is the first-line chemotherapy of choice in most patients with ovarian carcinoma.

However, patients with inherent or acquired cisplatin resistance often experience relapse. Therefore, novel therapies are urgently required to treat drug-resistant ovarian carcinoma. Here, we showed that compared to the non-functional traditional simultaneous treatment, sequential combination of Aurora B inhibitors followed by cisplatin synergistically enhanced apoptotic response in cisplatin-resistant OVCAR-8 cells. This effect was accompanied by the induction of polyploidy in a c-Myc -dependent manner, as c-Myc knockdown reduced the efficacy of the combination by suppressing the expression of Aurora B and impairing cellular response to Aurora B inhibitor, as indicated by the decreased polyploidy and hyperphosphorylation of histone H1.

Thus, our report reveals for the first time that sequential treatment of Aurora B inhibitors and cisplatin is essential to inhibit ovarian carcinoma by inducing polyploidy and downregulating c-Myc and that c-Myc is identified as a predictive biomarker to select cells responsive to chemotherapeutical combinations targeting Aurora B.

Collectively, these studies provide novel approaches to overcoming cisplatin chemotherapy resistance in ovarian cancer. Pretreatment of Aurora B inhibitors augment apoptotic effects of cisplatin. The synergy of Aurora B inhibitor with cisplatin is dependent on c-Myc expression. Distinct nuclear arrangement of active and inactive c-myc genes in control and differentiated colon carcinoma cells.

Using sequential RNA-DNA fluorescence in situ hybridization, the nuclear arrangement of both the active and inactive c-myc gene as well as its transcription was investigated in colon cancer HT cells induced to differentiate into enterocytes. Cytogenetic studies revealed the presence of two chromosomes 8 in HT cells, of which the one containing c-myc gene amplicons was substantially larger and easily distinguished from the normal chromosome.

This observation enabled detection of both activity and nuclear localization of c-myc genes in single cells and in individual chromosome territories. Our experiments demonstrate strikingly specific nuclear and territorial arrangements of active genes as compared with inactive ones: on the periphery of their territories facing to the very central region of the cell nucleus.

Nuclear arrangement of c-myc genes and transcripts was conserved during cell differentiation and, therefore, independent of the level of differentiation-specific c-myc gene expression. However, after the induction of differentiation, a more internal territorial location was found for the single copy c-myc gene of normal chromosome 8, while amplicons conserved their territorial topography. Polyglutamine poly Q disorders, such as Huntington's disease HD and spinocerebellar ataxias, represent a group of neurological disorders which arise due to an atypically expanded poly Q tract in the coding region of the affected gene.

Pathogenesis of these disorders inside the cells begins with the assembly of these mutant proteins in the form of insoluble inclusion bodies IBs , which progressively sequester several vital cellular transcription factors and other essential proteins, and finally leads to neuronal dysfunction and apoptosis. We have shown earlier that targeted upregulation of Drosophila myc dmyc dominantly suppresses the poly Q toxicity in Drosophila.

The present study examines the ability of the human c-myc proto-oncogene and also identifies the specific c-Myc isoform which drives the mitigation of poly Q -mediated neurotoxicity, so that it could be further substantiated as a potential drug target. We report for the first time that similar to dmyc, tissue-specific induced expression of human c-myc also suppresses poly Q -mediated neurotoxicity by an analogous mechanism.

Among the three isoforms of c-Myc , the rescue potential was maximally manifested by the full-length c-Myc 2 protein, followed by c-Myc 1, but not by c-Myc S which lacks the transactivation domain. Our study suggests that strategies focussing on the transactivation domain of c-Myc could be a very useful approach to design novel drug molecules against poly Q disorders. The general mechanism underlying the tumor suppressor activity of the Hippo signaling pathway remains unclear.

In this study, we explore the molecular mechanisms connecting the Hippo signaling pathway with glucose metabolism. The inhibition of lactate production and cellular proliferation induced by shikonin also depends on the Hippo pathway activity. In summary, regulation of glucose metabolism could serve as a new tumor suppressor mechanism orchestrated by the Hippo signaling pathway.

Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc : conditional regulation of c-myc transcription by temperature-sensitive v-abl. Retroviral expression vectors carrying the tyrosine kinase oncogenes abl, fms, src, and trk abrogate the requirements of murine myeloid FDC-P1 cells for interleukin-3 IL Factor-independent clones constitutively express c-myc in the absence of IL-3, whereas in parental cultures c-myc transcription requires the presence of the ligand.

To directly test the effect of a tyrosine kinase oncogene on c-myc expression, retroviral constructs containing three different temperature-sensitive mutants of v-abl were introduced into myeloid ILdependent FDC-P1 and 32D cells. At the permissive temperature, clones expressing temperature-sensitive abl behaved like wild-type abl-containing cells in their growth properties and expressed c-myc constitutively.

Temperature shift experiments demonstrated that both IL-3 abrogation and the regulation of c-myc expression correlated with the presence of functional v-abl. Induction of c-myc expression by reactivation of temperature-sensitive v-abl mimicked c-myc induction by IL-3 in that it did not require protein synthesis and occurred at the level of transcription, with effects on both initiation and a transcription elongation block. However, v-abl-regulated FDC-P1 cell growth differed from ILregulated growth in that c-fos and junB, which are normally induced by IL-3, were not induced by activation of v-abl.

In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously stage 4s-non-amplified. In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes. Their transcript levels were analyzed in primary neuroblastomas.

In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression. Evaluation of the antitumor effects of c-Myc -Max heterodimerization inhibitor F4 in ovarian cancer cells.

Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma. Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. Our objective was to evaluate the potential effects of small-molecule c-Myc inhibitor, F4, on ovarian carcinoma cells and the underlying mechanisms by which F4 exerts its actions.

Consistently, primary cultures of ovarian cancer treated with F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. The response to F4 was independent the level of c-Myc protein over-expression in primary cultures of ovarian carcinoma. These novel findings suggest that the growth of ovarian cancer cells is dependent upon c-MYC activity and that targeting c-Myc -Max heterodimerization could be a potential therapeutic strategy for ovarian cancer.

The critical targets that mediate the functions of oncogenic c-Myc in colorectal cancer have yet to be fully elucidated. Moreover, we provide a molecular basis for the synergistic combination of Wnt and mTOR inhibitors in treating colorectal cancer with elevated c-Myc. Cancer Res; 78 12 ; Acidosis is a biochemical hallmark of the tumor microenvironment.

Here, we report that acute acidosis decreases c-Myc oncogene expression in U human lymphoma cells. The level of c-Myc transcripts, but not mRNA or protein stability, contributes to c-Myc protein reduction under acidosis. Acidic pH alone is insufficient to reduce c-Myc expression, as it does not decrease c-Myc in H lung cancer cells expressing very low levels of pH-sensing G protein-coupled receptors GPCRs.

Instead, c-Myc is slightly increased by acidosis in H cells, but this increase is completely inhibited by ectopic overexpression of TDAG8. Collectively, our results identify a novel mechanism of c-Myc regulation by acidosis in the tumor microenvironment and indicate that modulation of TDAG8 and related pH-sensing receptor pathways may be exploited as a new approach to inhibit Myc expression. Both coding exons of the c-myc gene contribute to its posttranscriptional regulation in the quiescent liver and regenerating liver and after protein synthesis inhibition.

In vivo, the steady-state level of c-myc mRNA is mainly controlled by posttranscriptional mechanisms. Using a panel of transgenic mice in which various versions of the human c-myc proto-oncogene were under the control of major histocompatibility complex H-2Kb class I regulatory sequences, we have shown that the 5' and the 3' noncoding sequences are dispensable for obtaining a regulated expression of the transgene in adult quiescent tissues, at the start of liver regeneration, and after inhibition of protein synthesis.

These results indicated that the coding sequences were sufficient to ensure a regulated c-myc expression. In the present study, we have pursued this analysis with transgenes containing one or the other of the two c-myc coding exons either alone or in association with the c-myc 3' untranslated region.

We demonstrate that each of the exons contains determinants which control c-myc mRNA expression. Moreover, we show that in the liver, c-myc exon 2 sequences are able to down-regulate an otherwise stable H-2K mRNA when embedded within it and to induce its transient accumulation after cycloheximide treatment and soon after liver ablation. Finally, the use of transgenes with different coding capacities has allowed us to postulate that the primary mRNA sequence itself and not c-Myc peptides is an important component of c-myc posttranscriptional regulation.

Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth. The oncoprotein c-Myc is often overexpressed in cancer cells, and the stability of this protein has major significance in deciding the fate of a cell. Thus, targeting c-Myc levels is an attractive approach for developing therapeutic agents for cancer treatment.

This macrocyclic tetrapeptide also regulated PP2A by reducing the levels of its phosphorylated form which regulates the stability of cellular c-Myc protein. Thus [D-Trp]CJ, represents a new lead compound for the potential development of an effective treatment of prostate cancer.

According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women. The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc.

This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. The aim of the present study was to analyse c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process.

DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. The level of gene copy increase was measured using the Scion image software. The amplification of both c-Myc and c-erbB-2 was detected in Only one tumour specimen concomitantly showed increased gene copy number for both studied genes.

Interestingly, besides amplification, gene deletion was also detected The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the result of clonal evolution and selection.

Cell Competition is an interaction between cells for existence in heterogeneous cell populations of multicellular organisms. This phenomenon is involved in initiation and progression of cancer where heterogeneous cell populations compete directly or indirectly for the survival of the fittest based on differential gene expression. In Drosophila, cells having lower dMyc expression are eliminated by cell competition through apoptosis when present in the milieu of cells having higher dMyc expression.

Thus, we designed a study to develop c-Myc human homolog dependent in vitro cell competition model of human cancer cells. Cells with higher c-Myc were transfected with c-myc shRNA to prepare cells with lower c-Myc and then co-cultured with the same type of cells having a higher c-Myc in equal ratio. Cells with lower c-Myc showed a significant decrease in numbers when compared with higher c-Myc cells, suggesting "loser" and "winner" status of cells, respectively. During microscopy, engulfment of loser cells by winner cells was observed with higher expression of JNK in loser cells.

Furthermore, elimination of loser cells was prevented significantly, when co-cultured cells were treated with the JNK apoptosis inhibitor. Above results indicate elimination of loser cells in the presence of winner cells by c-Myc -dependent mechanisms of cell competition in human cancer cells.

This could be an important mechanism in human tumors where normal cells are eliminated by c-Myc -overexpressed tumor cells. Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells. Deciding appropriate therapy for multiple myeloma MM is challenging because of the occurrence of multiple chromosomal changes and the fatal nature of the disease. In the current study, gamabufotalin GBT was isolated from toad venom, and its tumor-specific cytotoxicity was investigated in human MM cells.

Further analysis showed that GBT especially evoked the ubiquitination and degradation of c-Myc protein, thereby globally repressing the expression of c-Myc target genes. An E3 ubiquitin-protein ligase, WWP2, was upregulated following JNK activation and played an important role in c-Myc ubiquitination and degradation through direct protein-protein interaction. Taken together, our study identified the potential of GBT as a promising therapeutic agent in the treatment of MM.

Mxi1 is a repressor of the c-Myc promoter and reverses activation by USF. A second B-HLH-LZ protein, Mxi1, is induced during terminal differentiation, and forms heterodimers with Max that also bind E-boxes but tether the mSin3 transcriptional repressor protein along with histone deacetylase thereby antagonizing Myc-dependent activation. We show that Mxi1 also antagonizes Myc by a second pathway, repression of transcription from the major c-myc promoter, P2.

Thus, induction of Mxi1 in terminally differentiating cells may block Myc function by repressing the c-myc gene P2 promoter, as well as by antagonizing Myc-dependent transactivation through E-boxes. Prostate cancer PCa cell radioresistance causes the failure of radiation therapy RT in localized or locally advanced disease.

Radiation was delivered using an x-6 MV photon linear accelerator. U in vivo activity alone or in combination with irradiation was determined in murine xenografts. The clinically approved compound trametinib used in vitro yielded the same effects as U on growth and C-Myc expression.

Notably, U and trametinib induced a drastic down-regulation of BMX, which is known to prevent apoptosis in cancer cells. We reported c-Myc induction drives cholestatic liver injury and cholangiocarcinoma CCA in mice.

We also showed induction of Maf proteins MafG and c-Maf contributed to cholestatic liver injury, whereas S-adenosylmethionine SAMe administration was protective. MAT1A expression fell in hepatocytes and bile duct epithelial cells during chronic cholestasis and in murine and human CCA.

The opposite occurred with c-Myc , MafG and c-Maf expression. The transcription factor c-Myc is an important regulator of cellular proliferation, differentiation and embryogenesis. While c-Myc can inhibit myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that c-Myc does not only inhibits myoblast differentiation but also promotes myoblast proliferation and muscle fibre hypertrophy. By performing chromatin immunoprecipitation and high-throughput sequencing ChIP-seq , we identified the genome-wide binding profile of c-Myc in skeletal muscle cells.

Interestingly, we identified four CAMs that can directly bind to the c-Myc 3' UTR and inhibit c-Myc expression, suggesting that a negative feedback loop exists between c-Myc and its target miRNAs during myoblast differentiation. Linc and linc are directly regulated by c-Myc , and both lincRNAs are involved in the regulation of myoblast proliferation and differentiation by competing for the binding of muscle differentiation-related miRNAs. Our findings do not only provide a genome-wide overview of the role the c-Myc plays in skeletal muscle cells but also uncover the mechanism of how c-Myc and its target genes regulate myoblast proliferation and differentiation, and muscle fibre hypertrophy.

Machiavelli wrote, in his famous political treatise Il Principe, about disrupting organization by planting seeds of dissension or by eliminating necessary support elements. Tumor cells do exactly that by disrupting the organized architecture of epithelial cell layers during progression from contained benign tumor to full-blown invasive cancer. However, it is still unclear whether tumor cells primarily break free by activating oncogenes powerful enough to cause chaos or by eliminating tumor suppressor genes guarding the order of the epithelial organization.

Studies in Drosophila have exposed genes that encode key regulators of the epithelial apicobasal polarity and which, upon inactivation, cause disorganization of the epithelial layers and promote unscheduled cell proliferation. The screen points out LKB1, which is a causal genetic lesion in Peutz-Jeghers cancer syndrome, a gene mutated in certain sporadic cancers and a human homologue of the fly polarity gene par We review the evidence linking Lkb1 protein to polarity regulation in the scope of our recent results suggesting a coupled role for Lkb1 as an architect of organized acinar structures and a suppressor of oncogenic c-Myc.

We finally present models to explain how Lkb1-dependent formation of epithelial architecture is coupled to suppression of normal and oncogene- induced proliferation. Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc. Erythropoietin Epo stimulation of erythroid cells results in the activation of several kinases and a rapid induction of c-myc expression.

Protein kinase C is necessary for Epo up-regulation of c-myc by promoting elongation at the 3'-end of exon 1. PKCepsilon mediates this signal. We now show that Epo triggers two signaling pathways to c-myc. LY also had no effect on Epo up-regulation of c-fos. LY blocked transcription of c-myc at exon 1. PD had no effect on transcription from exon 1 but, rather, blocked Epo- induced c-myc elongation at the 3'-end of exon 1.

These results identify two Epo signaling pathways to c-myc , one of which is PI3K-dependent operating on transcriptional initiation, whereas the other is mitogen-activated protein kinase-dependent operating on elongation.

Activation of protein kinase C induces nuclear translocation of RFX1 and down-regulates c-myc via an intron 1 X box in undifferentiated leukemia HL cells. The inhibition of Myc synthesis accounted for the drop in Myc protein, because PMA treatment had no effect on Myc turnover. Transfection of HL cells with myc reporter gene constructs showed that the RFX1-binding X box was required for the down-regulation of reporter gene expression by PMA.

These findings suggest that nuclear translocation and binding of RFX1 to the X box cause the down-regulation of myc expression, which follows acute PKC activation in undifferentiated HL cells. Cullin3 E3 ubiquitin ligase ubiquitinates a wide range of substrates through substrate-specific adaptors Bric-a-brac, Tramtrack, and Broad complex BTB domain proteins.

These E3 ubiquitin ligase complexes are involved in diverse cellular functions. Our recent study demonstrated that decreased Cullin3 expression induces glioma initiation and correlates with poor prognosis of patients with malignant glioma. However, the substrate recognition mechanism associated with tumorigenesis is not completely understood. Through yeast two-hybrid screening, we identified potassium channel tetramerization domain-containing 2 KCTD2 as a BTB domain protein that binds to Cullin3.

As an underlying mechanism for these KCTD2-mediated phenotypic changes, we demonstrated that KCTD2 interacts with c-Myc , which is a key stem cell factor, and causes c-Myc protein degradation by ubiquitination. As a result, KCTD2 depletion acquires GSC features and affects aerobic glycolysis via expression changes in glycolysis-associated genes through c-Myc protein regulation. This study describes a novel regulatory mode of c-Myc protein in malignant gliomas and provides a potential framework for glioma therapy by targeting c-Myc function.

Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Natural killer NK cells are lymphocytes with important anti-tumour functions. However, the mechanisms leading to this metabolic phenotype are unclear. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses.

These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function. The c-myc gene amplification observed in human tumors is likely to represent an activation mechanism aiming at an increased transcription level.

In order to evaluate the biological significance of this amplification in the malignant transformation the authors designed an experimental model that could possibly mimic this situation in vitro. They have constructed a series of plasmids which physically link the human c-myc gene to the bovine papilloma virus type 1 genome BPV1 and therefore should be maintained as amplified episomes upon transformation of rodent cells.

Immortal cell lines were established by transfection of the hybrid plasmids carrying either the complete BPV1 genome or the transforming region of the viral genome. The analysis of the established cell lines demonstrates that the transfected plasmids are present not as free copies as anticipated but rather integrated as tandem repeats.

They present data which strongly suggest that the immortalization capacity of the hybrid plasmids reflects the activation of the c-myc gene by the transactivable BPV1 enhancer. Although both the BPV1 early genes and the c-myc gene are actively transcribed, most of the cell lines do not display a transformed phenotype.

Structurally related pentacyclic triterpenoids methyl 2-cyano-3,dioxoolean-1,9-dienoate [bardoxolone-methyl Bar-Me ] and methyl 2-trifluoromethyl-3,dioxoolean-1,dienoate CF3DODA-Me contain 2-cyanoenone and 2-trifluoromethylenone moieties, respectively, in their A-rings and differ in the position of their en-one structures in ring C. In contrast, both Bar-Me and CF3DODA-Me induce reactive oxygen species in HL and Jurkat leukemia cells, inhibit cell growth, induce apoptosis and differentiation, and decrease expression of specificity proteins Sp 1, 3, and 4, and cMyc , and these effects are significantly attenuated after cotreatment with the antioxidant GSH.

In contrast to solid tumor—derived cells, cMyc and Sp transcriptions are regulated independently and cMyc plays a more predominant role than Sp transcription factors in regulating HL or Jurkat cell proliferation and differentiation compared with that observed in cells derived from solid tumors. Structurally related pentacyclic triterpenoids methyl 2-cyano-3,dioxoolean-1,9-dienoate [bardoxolone-methyl Bar-Me ] and methyl 2-trifluoromethyl-3,dioxoolean-1,dienoate CF 3 DODA-Me contain 2-cyanoenone and 2-trifluoromethylenone moieties, respectively, in their A-rings and differ in the position of their en-one structures in ring C.

In contrast, both Bar-Me and CF 3 DODA-Me induce reactive oxygen species in HL and Jurkat leukemia cells, inhibit cell growth, induce apoptosis and differentiation, and decrease expression of specificity proteins Sp 1, 3, and 4, and cMyc , and these effects are significantly attenuated after cotreatment with the antioxidant GSH.

In contrast to solid tumor-derived cells, cMyc and Sp transcriptions are regulated independently and cMyc plays a more predominant role than Sp transcription factors in regulating HL or Jurkat cell proliferation and differentiation compared with that observed in cells derived from solid tumors.

Since patients with MYCN-amplified neuroblastoma have a poor prognosis, targeting MYCN using small molecule inhibitors could represent a promising therapeutic approach. Our previous work also revealed that MYCN-inhibition leads to mitochondrial dysfunction resulting in accumulation of lipid droplets in neuroblastoma cells.

We also assessed their ability to induce apoptosis, neurite outgrowth and lipid accumulation in neuroblastoma cells. Importantly, G5 and F4 were the most efficient in inducing neuronal differentiation and lipid accumulation in MYCN-amplified neuroblastoma cells.

Together our data demonstrate MYCN-binding properties for a selection of small molecules, and provide functional information that could be of importance for future development of targeted therapies against MYCN-amplified neuroblastoma. To analyse the role of Pasteurella haemolytica Leukotoxin LKT in the mechanism of apoptotic cell death of bovine lymphocytes, we evaluated DNA fragmentation and p53 and c-myc expression.

DNA fragmentation was analysed by electrophoresis on Agarose gel. DNA strand breaks in individual apoptotic cells were also detected by an in situ Terminal deoxy nucleotidyl Transferase TdT. The greatest apoptotic effect was obtained using LKT at a concentration of 0. The results show that p53 and c-myc activation by LKT is correlated with apoptosis of bovine lymphocytes and monocytes. Our data suggest that LKT may have an important role in the bacterial virulence of Pasteurella haemolytica.

Proteomic Characterization of the World Trade Center dust-activated mdig and c-myc signaling circuit linked to multiple myeloma. Several epidemiological studies suggested an increased incidence rate of multiple myeloma MM among first responders and other individuals who exposed to World Trade Center WTC dust.

An increased mdig expression in MM bone marrow was observed, which is associated with the disease progression and prognosis of the MM patients. Taken together, these data suggest that WTC dust may be one of the key etiological factors for those who had been exposed for the development of MM by activating mdig and c-myc signaling circuit linked to the ILJAK-STAT3 pathway essential for the tumorigenesis of the malignant plasma cells.

The dependence of cancer on overexpressed c-MYC and its predisposition for polyploidy represents a double puzzle. We address this conundrum by cross-species transcription analysis of c-MYC interacting genes in polyploid vs. Gene-by-gene transcriptome comparison and principal component analysis indicated that c-MYC interactants are significantly overrepresented among ploidy-associated genes.

Protein interaction networks and gene module analysis revealed that the most upregulated genes relate to growth, stress response, proliferation, stemness and unicellularity, as well as to the pathways of cancer supported by MAPK and RAS coordinated pathways. Metabolic pathway analysis also revealed the EMT-linked features, such as global proteome remodeling, oxidative stress, DNA repair and Warburg-like energy metabolism. Genes associated with apoptosis, immunity, energy demand and tumour suppression were mostly down-regulated.

Noteworthy, despite the association between polyploidy and ample features of cancer, polyploidy does not trigger it. Possibly it occurs because normal polyploidy does not go that far in embryonalisation and linked genome destabilisation. In general, the analysis of polyploid transcriptome explained the evolutionary relation of c-MYC and polyploidy to cancer.

Non-transmissible Sendai virus vector encoding c-myc suppressor FBP-interacting repressor for cancer therapy. Antitumor efficacy in a mouse xenograft model was also examined. Thus, FIR expressing vectors are potentially applicable for cancer therapy.

Thus, both the valuable effects and side effects of exogenous FIR stimuli should be tested for future clinical application. HA-FIR suppressed. Carbazole ligands as c-myc G-quadruplex binders. The interactions of c-myc G-quadruplex with three carbazole derivatives were investigated by UV-Vis spectrophotometry, fluorescence, CD spectroscopy, and molecular modeling. The results showed that a combination of carbazole scaffold functionalized with ethyl, triazole and imidazole groups resulted in stabilization of the intramolecular G-quadruplex formed by the DNA sequence derived from the NHE III 1 region of c-myc oncogene Pu Binding to the G-quadruplex Pu22 resulted in the significant increase in fluorescence intensity of complexed ligands All ligands were capable of interacting with G4 DNA with binding stoichiometry indicating that two ligand molecules bind to G-quadruplex with comparable affinity, which agrees with binding model of end-stacking on terminal G-tetrads.

New insights into the molecular signature of these rare cancers. The molecular alterations of pancreatic acinar cell carcinomas ACCs and mixed acinar-neuroendocrine carcinomas MANECs are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes.

Protein expression was immunohistochemically investigated using a specific monoclonal anti- c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. Six cases Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy.

Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs. Mechanism of estrogen activation of c-myc oncogene expression.

The estrogen receptor complex is a known trans-acting factor that regulates transcription of specific genes through an interaction with a specific estrogen-responsive cis-acting element ERE. In previous studies we have shown that in estrogen-responsive human breast cancer cells estrogen rapidly activates c-myc expression.

This activated expression occurs through enhanced transcription and does not require the synthesis of new protein intermediates; therefore, an ERE is present in the human c-myc gene regulatory region. They were used in transient transfection studies in MCF-7 and HeLa cells co-transfected with an estrogen receptor expression vector. These studies reveal that all constructs containing the P2 promoter region exhibited estrogen-regulated CAT expression and that a bp region upstream and encompassing the P2 TATA box is necessary for this activity.

Analysis of this bp region failed to identify a cis-acting element with sequences resembling the consensus ERE; however, co-transfection studies with mutant estrogen receptor expression vectors showed that the DNA-binding domain of the receptor is essential for estrogen-regulated CAT gene expression. To explain these results we propose a new mechanism of estrogen trans-activation in the c-myc gene promoter.

Pre-clinical analysis of changes in intra-cellular biochemistry of glioblastoma multiforme GBM cells due to c-Myc silencing. JQ1 is essentially a Myc inhibitor. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition. The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc , Bcl-2, and Akt.

The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole. The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future.

Effects of alcohol on c-Myc protein in the brain. Alcoholism is a disorder categorized by significant impairment that is directly related to persistent and extreme use of alcohol. The effects of alcoholism on c-Myc protein expression in the brain have been scarcely studied. This is the first study to investigate the role of different characteristics of alcoholism in c-Myc protein levels in the brain. We analyzed c-Myc protein in the hypothalamus and amygdala from four different animal models of alcohol abuse.

We also observed increases in c-Myc protein exposure in animals that are genetically predisposed to alcohol and methamphetamine abuse. Lastly, c-Myc protein was increased in animals that were acutely exposed to methamphetamine when compared to control treated animals.

The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Aberrant stabilization of c-Myc contributes to many human cancers. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc.

This USP36 regulation of c-Myc occurs in the nucleolus. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. High expression levels of USP36 are found in a subset of human breast and lung cancers. However, it remains elusive how they are regulated in HCC.

We investigated the mechanisms of regulation of c-myc , c-fos, and c-jun at the early stages of liver regeneration in mice. We show that the transient increase in steady-state levels of c-myc mRNA at the start of liver regeneration is most probably regulated by posttranscriptional mechanisms. Although there was a marked increase in c-myc transcriptional initiation shortly after partial hepatectomy, a block in elongation prevented the completion of most transcripts.

To gain further information on the mechanism of regulation of c-myc expression during liver regeneration, we used transgenic mice harboring the human c-myc gene driven by the H-2K promoter. In these animals, the murine c-myc responded to the growth stimulus generated by partial hepatectomy, whereas the expression of the transgene was constitutive and did not change in the regenerating liver. However, the mRNA from both genes increased markedly after cycloheximide injection, suggesting that the regulation of c-myc mRNA abundance in the regenerating liver differs from that occurring after protein synthesis inhibition.

Furthermore, we show that in normal mice c-fos and c-jun mRNA levels and transcriptional rates increase within 30 min after partial hepatectomy. Nevertheless, for both c-fos and c-jun, changes in steady-state mRNA detected after partial hepatectomy were much greater than the transcriptional increase. SIRT1 has been found to function as a Class III deacetylase that affects the acetylation status of histones and other important cellular nonhistone proteins involved in various cellular pathways including stress responses and apoptosis.

The data are representative of three individual experiments. Ashton, Gabrielle H. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer. Protein-protein interaction is an essential biochemical event that mediates various cellular processes including gene expression, intracellular signaling, and intercellular interaction.

Understanding such interaction is key to the elucidation of mechanisms of cellular processes in biology and diseases. Osteosarcoma is the most common primary malignancy in bone. Patients who respond poorly to induction chemotherapy are at higher risk of adverse prognosis. The molecular basis for such poor prognosis remains unclear. Recently, increasing evidence has suggested decreased expression of miRa is observed in a number of cancer types, including human osteosarcoma, and decreased miRa is involved in drug resistance.

However, the underlying molecular mechanisms of decreased miRa on cisplatin chemoresistance in osteosarcoma has not been reported. Osteosarcoma U2OS cells were transfected with miRa mimics for 48 h, then the cells were treated with 3. Using siRNA targeting c-Myc and Bim to examine the relation between miRa, c-Myc and Bim expression exposure to cisplatin on cisplatin- induced apoptosis.

Our data indicated that miRa enhanced the sensitivity to cisplatin by upregulation of c-Myc and Bim pathway. Clinicopathological significance of c-MYC in esophageal squamous cell carcinoma. Esophageal squamous cell carcinoma is one of the most common malignant tumors. The oncogene c-MYC is thought to be important in the initiation, promotion, and therapy resistance of cancer. In this study, we aim to investigate the clinicopathologic roles of c-MYC in esophageal squamous cell carcinoma tissue.

This study is aimed at discovering and analyzing c-MYC expression in a series of human esophageal tissues. A total of 95 esophageal squamous cell carcinoma samples were analyzed by the western blotting and immunohistochemistry techniques.

Then, correlation of c-MYC expression with clinicopathological features of esophageal squamous cell carcinoma patients was statistically analyzed. In most esophageal squamous cell carcinoma cases, the c-MYC expression was positive in tumor tissues. The positive rate of c-MYC expression in tumor tissues was There was a statistical difference among adjacent normal tissues, atypical hyperplasia tissues, and tumor tissues.

Overexpression of the c-MYC was detected in The positive rate of c-MYC expression was The positive rate of c-MYC was The c-MYC was. In silico identification of novel ligands for G-quadruplex in the c - MYC promoter. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c - MYC. Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene.

In conclusion, combined virtual screening methods were successfully used for discovery of selective c - MYC promoter G-quadruplex binders with anticancer activity. Id2 leaves the chromatin of the E2F4—pcontrolled c-myc promoter during hepatocyte priming for liver regeneration. The Id inhibitor of DNA binding or inhibitor of differentiation helix—loop—helix proteins are involved in the regulation of cell growth, differentiation and cancer. The fact that the molecular mechanisms of liver regeneration are not completely understood prompted us to study the fate of Id2 in proliferating liver.

Id2 increases in liver regeneration after partial hepatectomy, following the early induction of its gene. Co-immunoprecipitation shows that Id2 forms a complex with E2F4, p and mSin3A in quiescent liver and all these components are present at the c-myc promoter as shown using ChIP chromatin immunoprecipitation.

Moreover, as the G0—G1 transition progresses, Id2 and HDAC again bind the c-myc promoter concomitantly with the repression of this gene. The time course of c-myc binding to the Id2 promoter, as determined by ChIP assays is compatible with a role of the oncoprotein as a transcriptional inducer of Id2 in liver regeneration. Immunohistochemical analysis shows that Id2 also increases in proliferating hepatocytes after bile duct ligation.

In this case, the pattern of Id2 presence in the c-myc promoter parallels that found in regenerating liver. Our results may suggest a control role for Id2 in hepatocyte priming, through a p dissociation-independent regulation of c-myc. Gliomas are among the most frequent adult primary brain tumors. Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival.

However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 RH mutants in both univariate and multivariate analyses. In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas. A multicolour flow cytometric assay for c-MYC protein in B-cell lymphoma. The relationship between c-MYC protein expression and the presence of a c-MYC gene rearrangement in aggressive and high-grade lymphomas was also assessed.

We have developed a reliable multicolour FCM assay to detect c-MYC expression suitable for clinical laboratories that should be helpful to accurately quantify c-MYC expression in B-cell lymphomas. No commercial use is permitted unless otherwise expressly granted. Metabolic labeling of nascent transcribed mRNA indicated that this was primarily a transcription-mediated event.

These data support a model in which high levels of endogenous c-Myc activity induced early after primary B cell infection directly repress LMP1 transcription. During the latent life cycle, EBV expresses a set of viral oncoproteins and noncoding RNAs with the potential to promote cancer. Critical among these is the viral latent membrane protein LMP1.

Prior work suggests that LMP1 is essential for EBV to immortalize B cells, but our recent work indicates that LMP1 is not produced at high levels during the first few weeks after infection. Here we show that transcription of the LMP1 gene can be negatively regulated by a host transcription factor, c-Myc. Ultimately, understanding the regulation of EBV oncogenes will allow us.

Induction of the c-myc protooncogene following antigen binding to hapten-specific B cells. Considerable controversy has centered on the role that the surface immunoglobulin sIg receptor for antigen plays during the induction of B cell activation. However, the authors have recently demonstrated that antigen binding to such hapten-specific B cells does result in the initiation of the membrane phosphatidylinositol cycle.

At that time, total cellular RNA was isolated and subsequently analyzed by either dot blots or Northern gel techniques. The results indicate that hapten carrier stimulation of the hapten-specific B cells induces enhanced transcription of the c-myc gene. These observations lend further support to the premise that antigen binding to the sIg receptor results in the transduction to the cell of important signals and implicates the active participation of sIg during the process of antigen-mediated B cell activation.

Evaluation of NKX3. The dog can be an interesting model for human prostatic disease, and yet only one previous research study has shown deregulation of NKX3. To address the expression of NKX3. We observed that NKX3. We found a positive correlation between NKX3. Interestingly, a negative correlation NKX3.

As in humans, these two genes and proteins were found to be related to canine prostate cancer. However, in contrast from what is observed in humans, in canine PC samples, the downregulation of NKX3. A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice. Malignant B cells responding to external stimuli are likely to gain a growth advantage in vivo. These cells may therefore maintain surface CD19 expression to amplify transmembrane signals and promote their expansion and survival.

In mechanistic studies, constitutive c-Myc expression enhanced CD19 expression and phosphorylation on active sites. Reciprocally, CD19 expression in c-Myc Tg B cells enhanced c-Myc phosphorylation at regulatory sites, sustained higher c-Myc protein levels, and maintained a balance of cyclin D2 expression over that of cyclin D3. These findings define a new and novel c-Myc :CD19 regulatory loop that positively influences B cell transformation and lymphoma progression.

Course of c-myc mRNA expression in the regenerating mouse testis determined by competitive reverse transcriptase polymerase chain reaction. The c-myc proto-oncogene is a reliable marker of the "G0-early G1" transition, and its down-regulation is believed to be necessary to obtain cellular differentiation. In murine spermatogenesis, the level of c-myc transcripts does not correlate with the rate of cellular division.

Proliferative status was determined by histone H3 Northern blot analysis. An increasing number of copies were noted up to 10 days, but promptly decreased to the base level found for irradiated mice from 13 to 60 days. Interestingly, the expression of histone H3 detected S phase only in testes at 60 days from damage. Their binding to DNA requires homo- or heterodimerization via alpha-helical domains, which generally do not contain obvious binding sites for small molecules.

We have identified two small molecules, dubbed Mycro1 and Mycro2, which inhibit the protein-protein interactions between the bHLHZip proteins c-Myc and Max. Mycros inhibit c-Myc -dependent proliferation, gene transcription, and oncogenic transformation in the low micromolar concentration range.

Our data support the idea that dimeric transcription factors can be druggable even in the absence of obvious small-molecule binding pockets. The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells.

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Na apresentao dos comentrios de Mriam Leito so freqentes interpelaes ou questionamentos feitos pelos apresentadores durante sua exposio. A jornalista em muitos momentos interrompida, h sobreposio de vozes e gaguejos, situaes comuns num dilogo normal. A jornalista faz uso de recursos expressivos como gestos com as mos e meneios de cabea para enfatizar seus argumentos.

A estrutura de apresentao do comentrio fixa. Na sequncia, o telespectador v entre em quadro o jornalista Joelmir Beting, em plano mdio,sentado, a bancada tendo ao fundo um cenrio que remete idia de uma redao de jornalismo. Tanto o cenrio quanto o enquadramento so fixos.

Uma caractersti7. Um telespectador atento pode perceber isso, pelo fato de que um selo escrito Ao vivo retirado da tela durante a exposio do comentarista. No comentrio de Joelmir Beting o olhar do jornalista dirigido diretamente para a cmera, como se estivesse fitando e conversando com o telespectador. Seu timbre de voz forte e compassado. Por vezes, possvel perceber inflexes de ironia em sua voz.

Na fala de Machado, o Banco Central a fonte da informao que Mriam iria comentar. Pelo comentrio de Mriam Leito, o telespectador tem uma idia positiva sobre o anncio da taxa de juros pelo Banco Central. Apesar da ressalva de que os juros so altssimos, Mriam salienta que a inflao est cedendo e que o medo da inflao tambm comea a ceder. A jornalista cita como exemplo a compra de um aparelho de 8.

No decorrer do comentrio, o apresentador Renato Machado fala de uma conversa que teria tido com um amigo economista alertando de que o Brasil pode ser afetado por uma crise externa. Mriam concorda com esta posio e afirma que o Brasil no poupa e investe pouco e por isso pode ficar vulnervel a crises externas.

Percebe-se durante o comentrio de Mriam, uma preocupao de emprestar um tom de conversa anlise, trazendo exemplos como a compra do aparelho de TV que pudessem ser entendidos pelo telespectador comum. J no incio de sua explanao, Joelmir d o tom de sua avaliao, fala de uma elevao da taxa de juros num tom alarmista, que atenuado pela afirmao de que j era esperado pelo mercado.

E mais adiante faz uma avaliao crtica, afirmando que outros segmentos da sociedade tambm esto insatisfeitos com o aumento da taxa de juros. De certa forma, introduz a idia de que o vice-presidente no concordaria com a conduta adota pela equipe econmica do governo. A idia que trazida pelo texto sentado numa dvida pblica de um governo inoperante e estagnado, que nada faz para mudar a situao. O riso sarcstico dissimulado, mas presente, refora uma situao de que o governo no teria competncia para administrar o pas: um caso nico: o devedor eleva o juros da prpria dvida.

Na viso de Mriam Leito, houve uma melhora na situao vivida no pas, o que fez com que o juros s aumentasse somente zero ponto cinco pontos percentuais, abaixo do previsto anteriormente. J na avaliao de Joelmir o aumento reflete a inoperncia do governo e afirma categoricamente que setores da sociedade empresrios, trabalhadores e consumidores fizeram crticas contra o aumento. Em seu texto, Beting evidencia o despreparo e a situao nica de um devedor que aumenta os juros da prpria dvida.

No est evidente em nenhum dos comentrios quais foram as fontes utilizadas para a apurao das informaes. Na fala de Renato, ele cita um amigo economista, Mriam fala do Banco Central, Joelmir menciona empresrios, trabalhadores e consumidores, porm ningum nomeia as pessoas envolvidas.

H uma falta de preciso na identificao dos atores que circulam no processo. Em nenhum momento, contextualizada a informao sobre a relao dos rgos citados com a informao fornecida. O carter informativo que caracterizaria a presena de um comentrio econmico inserido no telejornal no cumpriria o seu papel fundamental. Os dados coletados ainda no so suficientes para uma anlise conjuntural da presena do jornalismo econmico no telejornalismo, nem das linhas editoriais adotadas pelos programas ou pelos comentaristas.

A pesquisa encontra-se em fase inicial, porm as primeiras leituras efetuadas j denunciam que o tema proposto pode revelar muito sobre a cobertura jornalstica da rea econmica no telejornalismo brasileiro e possivelmente as construes de sentido que podem ser apresentadas pelo texto jornalstico. Anlise de Contedo. Lisboa: Edies 70, A linguagem na reportagem econmica.

I Seminrio de Tcnica de Jornalismo. Rio de Janeiro: ABI, ?. Jornalismo econmico. So Paulo: Contexto, So Paulo: Summus Editorial, O papel do jornal: uma releitura. Barreiras na produo de conhecimento pelo jornalismo econmico. Estudos em Jornalismo e Mdia. III, N.

Jornalismo na era virtual: ensaios sobre o colapso da razo tica. Construtores do Jornalismo Econmico: da cotao do boi ao congelamento de preos. So Paulo: cone Propostas Metodolgicas para a Anlise de Telejornais. Curitiba, CD ROM. Entrevista: a arte e as histrias dos maiores entrevistadores da televiso brasileira.

So Paulo: Globo, Pular no carrossel. Anterior no carrossel. Enviado por Cynthia Mariah Barreto Correia. Denunciar este documento. Baixar agora. Pesquisar no documento. SBPJor Associao Brasileira de Pesquisadores em Jornalismo VIII Encontro Nacional de Pesquisadores em Jornalismo Universidade Federal do Maranho, So Lus , novembro o de Vertentes do jornalismo econmico no telejornalismo brasileiro: as colunas de Mriam Leito e Joelmir Beting Edna de Mello Silva 1 Resumo: O artigo se prope a trazer uma breve reviso de literatura sobre o histrico, a linguagem e os desafios do jornalismo econmico no Brasil.

J Dines , p. Concluses preliminares notria a diferena de abordagem sobre o tema do anncio do aumento da taxa de juros entre os dois comentaristas. Paula Miranda. Lucas Seixas. Angela Bloom. Luiz Cunha. Ronnie Turrini. Osmar Alves Bocci. Paulo Silva Cardoso. Vitor Colares. Candida Oliveira. Clayton Henrique. Geilson Fernandes. Jefferson Donizetti Oliveira. Rita Pinote. Valdinete Ribeiro. Mais de Cynthia Mariah Barreto Correia. Cynthia Mariah Barreto Correia. Mariana Guedes. Interatividade - Uma Ferramenta Para o Jornalismo.

Murian Ribeiro. Thiago Dutra. Marcelobernardo Portugues Analisedetextos Modulo01 Vinicius Nascimento Bittencourt. He made a tomography early in the morning. In some minutes the doctor a fanatic Corinthians supporter said another giant could no longer rise again. In the day after to the diabolic second-class division my father started to go to Heaven.

The chances to recover from an autoimmune disease were not so good. They became almost impossible with the bleeding of his privileged brain. Irrigated and ventilated as too few among those who know and recognize him. Beloved and cherished for those not too few that had the privilege to know him. Do I need to say anything else to the best Babbo in the world that turned to be the best Nonno in the Universe? I need. But I don't know. Usually he knew everything. When he didn't knew, he invented with the same class as he talked what he knew.

Every father looks like that to his son. But a journalist's father to someone which is also a journalist gets even more orphan. I have never seen my father as a super-hero. Only as a super human. But I could never realize he would get ill and weak in flesh. I have never admitted we could lose the one that made us only gain. He taught me so many things I couldn't describe them. One of them is, not all words are needed to be said. They should only be thought. Those who talks about what thinks, doesn't think about what he talks.

Those who feels what he talks doesn't need to say it. But, today, I need to thank for my 46 years. For the 49 years of love from my mother. For his 75 years. More than everything, for the affection from the people that know him — therefore like him.

And specially for the people who don't know him — and some who cried like he was an old friend. I've learned a thing from you, babbo. Before become a great journalist it is needed to be a great person. I have learned from him I don't need to work to be a great professional. I need to try to be a great person. As you did both. Excuse me, but I won't cry. I cry for everything.

Because of that I always cry for the family. Palmeiras, loves, pains, colours, songs. But I won't cry for everything more than anything in the world, my parents. My parents which could be also called my mothers [note 4] were always ready.

A gift from God. My father never missed me even when absent by his work. I never missed him because he had that wonderful woman, Mrs. According to Mr. Joelmir, the second biggest thing in his life. Because the first one always was his love he felt for her since When they became a family. My brother and I. Sons of the radio. Sons of a pioneer, respected economics' journalist, a recognized, innovator TV anchorman, a communication master, brilliant and labourer.

I always knew I would never be in my profession nothing even closer he was. Because too few were too good in his field.

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The formation of isoprene SOA is influenced largely by anthropogenic emissions through multiphase chemistry of its multigenerational oxidation products. Considering the abundance of isoprene SOA in the troposphere, understanding mechanisms of adverse health effects through inhalation exposure is critical to mitigating its potential impact on public health. In this study, we assessed the effects of isoprene SOA on gene expression in human airway epithelial cells BEAS - 2 B through an air-liquid interface exposure.

Gene expression profiling of 84 oxidative stress and inflammation-associated human genes was performed. Our results show that the expression levels of 29 genes were significantly altered upon isoprene SOA exposure under noncytotoxic conditions p cell line. Together with detailed characterization of SOA constituents, this study reveals the impact of isoprene SOA exposure on lung responses and highlights the importance of further understanding its potential health outcomes.

Hexavalent chromium Cr VI promotes lung injury and pulmonary diseases through poorly defined mechanisms that may involve the silencing of inducible protective genes. The current study investigated the hypothesis that Cr VI actively signals through a signal transducer and activator of transcription 1 STAT1 —dependent pathway to silence nickel Ni —induced expression of vascular endothelial cell growth factor A VEGFA , an important mediator of lung injury and repair. This study demonstrates that metal-stimulated signaling cascades interact to regulate transcription and induction of adaptive or repair responses in airway cells.

Hexavalent chromium [Cr VI ] compounds e. Inhalation is a major route of exposure which directly exposes the bronchial epithelium. Previous studies with non-cancerous human bronchial epithelial cells BEAS - 2 B demonstrated that Cr VI treatment results in the irreversible inhibition of thioredoxin reductase TrxR and the oxidation of thioredoxins Trx and peroxiredoxins Prx.

Nitration of tyrosine residues of TrxR was not observed following Cr VI treatment, further ruling out peroxynitrite as a significant contributor to the irreversible inhibition of TrxR. Overall, the redox stress that results from Cr VI exposure shows selectivity for key proteins which are known to be important for redox signaling, antioxidant defense, and cell survival. Effects of bile acids on human airway epithelial cells : implications for aerodigestive diseases. Gastro-oesophageal reflux and aspiration have been associated with chronic and end-stage lung disease and with allograft injury following lung transplantation.

This raises the possibility that bile acids may cause lung injury by damaging airway epithelium. The aim of this study was to investigate the effect of bile acid challenge using the immortalised human bronchial epithelial cell line BEAS - 2 B. A h challenge evaluated the effect of individual primary and secondary bile acids. Lithocholic acid, deoxycholic acid, chenodeoxycholic acid and cholic acid were successfully used to stimulate cultured BEAS - 2 B cells at different concentrations.

Aspiration of bile acids could potentially cause cell damage, cell death and inflammation in vivo. This is relevant to an integrated gastrointestinal and lung physiological paradigm of chronic lung disease, where reflux and aspiration are described in both chronic lung diseases and allograft injury. Investigating mitochondrial dysfunction in human lung cells exposed to redox-active PM components. Exposure to ambient particulate matter PM causes cardiopulmonary morbidity and mortality through mechanisms that involve oxidative stress.

We previously reported that 1,2-NQ increases mitochondrial H 2 O 2 production through an unidentified mechanism. We sought to characterize the effects of 1,2-NQ exposure on mitochondrial respiration as a source of H 2 O 2 in human airway epithelial cells. We measured the effects of acute exposure to 1,2-NQ on oxygen consumption rate OCR in the human bronchial epithelial cell line BEAS - 2 B and mitochondrial preparations using extracellular flux analysis. Complex-specific assays and NADPH depletion by glucose deprivation distinguished between mitochondrial and non-mitochondrial oxygen utilization.

Similar effects were observed with the environmentally relevant redox-cycling quinones 1,4-naphthoquinone and 9,phenanthrenequinone, but not with quinones that do not redox cycle, such as 1,4-benzoquinone. In mitochondrial preparations, 1,2-NQ caused a decrease in Complex I-linked substrate oxidation, suggesting impairment of pyruvate utilization or transport, a novel mechanism of mitochondrial inhibition by an environmental exposure. This study also highlights the methodological utility and challenges in the use of extracellular flux analysis to elucidate the mechanisms of action of redox-active electrophiles present in ambient air.

Published by Elsevier Inc. X-irradiation of human bronchial cancer cells causes the bystander effects in normal bronchial cells in vitro. Using X radiation commonly used in radiotherapy of cancers we investigated bystander interactions between human cells : irradiated A bronchial carcinoma human cells and non irradiated BEAS - 2 B normal bronchial epithelial cells. Non irradiated cells were incubated in medium transferred from irradiated A cells ICM-irradiation conditioned medium for 48h and next the chromosomal damage and apoptosis were estimated.

Conditioned medium collected from irradiated cancer cells induced in non irradiated cells of the same line as well as in BEAS - 2 B normal cells genetic changes such as micronuclei, chromatid and chromosomal breaks and condensation of chromatin characteristic for processes of apoptosis. The presented results in this study could have implications for human radiation risk and in evaluating the secondary effects of radiotherapy. Highlights: Black-Right-Pointing-Pointer Hyperoxia induces apoptosis and chitinase 3-like 1 expression in human airway epithelial cells.

Black-Right-Pointing-Pointer Presence of chitinase 3-like 1 affects airway epithelial cell death after hyperoxic exposure. Recently, the role of chitinase 3-like 1 CHI3L1 , a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models.

However, the role of CHI3L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CHI3L1 in this process are poorly understood. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy. CHI3L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CHI3L1 overexpression promoted cell death after hyperoxia exposure.

Pathway modeling of the protein differential expression showed that CuO NP affect proteins relevant in cellular function and maintenance, protein synthesis, cell death and survival, cell cycle and cell morphology.

Some of the signaling pathways represented by BEAS - 2 B proteins responsive to the NP included mTOR signaling, protein ubiquitination pathway, actin cytoskeleton signaling and epithelial adherens junction signaling. Follow-up experiments showed that CuO NP altered actin cytoskeleton, protein phosphorylation and protein ubiquitination level.

Gene expression analysis uncovers novel Hedgehog interacting protein HHIP effects in human bronchial epithelial cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected.

BEAS - 2 B cells did not differentiate or develop tight junctions. These data highlight the challenges in working with primary cell models and the need for careful characterisation and selection of systems to answer specific research questions. Toxicological responses of exhaust emissions of biodiesel are different due to variation in methods of generation and the tested biological models. A cytotoxicity assay and cytokine secretion experiments were evaluated in human bronchial epithelial cells BEAS - 2 B.

Cells were exposed to polar acetone and nonpolar hexane extracts from particles obtained from fuel exhaust: fossil diesel B5 , pure soybean biodiesel B , soybean biodiesel with additive BA and ethanol additive EtOH. Biodiesel and its additives exhibited higher organic and inorganic constituents on particles when compared to B5. In fact quite the opposite, a cell proliferation effect induced by the B and BA extracts is reported.

A small increase in concentrations of inflammatory mediators Interleukin-6, IL-6; and Interleukin-8, IL-8 in the medium of biodiesel-treated cells was observed, however, no statistical difference was found. An interesting finding indicates that the presence of metals in the nonpolar hexane fraction of biodiesel fuel B represses cytokine release in lung cells. This was revealed by the use of the metal chelator. Biodiesel from soybean promotes cell proliferation in vitro.

Results suggest that metals associated with biodiesel's organic constituents might play a significant role in molecular mechanisms associated to cellular proliferation and immune responses. Published by Elsevier Ltd. Analysis of nicotine-induced DNA damage in cells of the human respiratory tract. Epithelium of the upper and lower airways is a common origin of tobacco-related cancer. The main tobacco alkaloid nicotine may be associated with tumor progression.

The potential of nicotine in inducing DNA mutations as a step towards cancer initiation is still controversially discussed. Different subtypes of nicotinic acetylcholine receptors nAChR are expressed in human nasal mucosa and a human bronchial cell line representing respiratory mucosa as a possible target for receptor-mediated pathways. In the present study, both cell systems were investigated with respect to DNA damage induced by nicotine and its mechanisms. Specimens of human nasal mucosa were harvested during surgery of the nasal air passage.

After enzymatic digestion over night, single cells were exposed to an increasing nicotine concentration between 0. DNA damage was assessed using the alkali version of the comet assay. Dose finding experiments for mecamylamine to evaluate the maximal inhibitory effect were performed in the human bronchial cell line BEAS - 2 B with an increasing mecamylamine concentration and a constant nicotine concentration. After 1h of nicotine exposure with 0. Further co-incubation experiments with mecamylamine and NAC were performed using 1.

The strongest inhibitory effect was measured at 1. Both, the antioxidant NAC at a concentration of 1. A nicotine-induced increase or decrease in. Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin.

However, the exact role of Bit1 in regulating malignant growth and transformation of human lung epithelial cells , which are origin of most forms of human lung cancers, has not been examined. To this end, we have downregulated the endogenous Bit1 expression in the immortalized non-tumorigenic human bronchial epithelial BEAS - 2 B cells. The loss of Bit1-induced transformed phenotypes was in part attributable to the repression of E-cadherin expression since forced exogenous E-cadherin expression attenuated the malignant phenotypes of the Bit1 knockdown cells.

Importantly, we show that the loss of Bit1 expression in BEAS - 2 B cells resulted in increased Erk activation, which functions upstream to promote TLE1-mediated transcriptional repression of E-cadherin. These collective findings indicate that loss of Bit1 expression contributes to the acquisition of malignant phenotype of human lung epithelial cells via Erk activation-induced suppression of E-cadherin expression. A particular challenge for nanotoxicology is the evaluation of the biological fate and toxicity of nanomaterials that dissolve in aqueous fluids.

Zinc oxide nanomaterials are of particular concern because dissolution leads to release of the toxic divalent zinc ion. Although dissolved zinc ions have been implicated in ZnO cytotoxicity, direct identification of the chemical form of zinc taken up by cells exposed to ZnO nanoparticles, and its intracellular fate, has not yet been achieved.

We combined high resolution X-ray spectromicroscopy and high elemental sensitivity X-ray microprobe analyses to determine the fate of ZnO and less soluble iron-doped ZnO nanoparticles following exposure to cultures of human bronchial epithelial cells , BEAS - 2 B. We complemented two-dimensional X-ray imaging methods with atomic force microscopy of cell surfaces to distinguish between nanoparticles that were transported inside the cells from those that adhered to the cell exterior.

The data suggest cellular uptake of ZnO nanoparticles is a mechanism of zinc accumulation in cells. These results corroborate a model for ZnO nanoparticle toxicity that is based on nanoparticle uptake followed by intracellular dissolution. Prediction of delivery of organic aerosols onto air-liquid interface cells in vitro using an electrostatic precipitator. To better characterize biological responses to atmospheric organic aerosols, the efficient delivery of aerosol to in vitro lung cells is necessary.

To augment in vitro assessment using the ESP exposure device, the particle dose was predicted for various sampling parameters such as particle size, ESP deposition voltage, and sampling flowrate. The dose model was evaluated against the experimental measured mass of collected airborne particles. The high flowrate used in this study increased aerosol dose but failed to achieve cell stability. The ESP device and the resulting model were applied to in vitro studies i.

Abiotic stress of ambient cold temperature regulates the host receptivity to pathogens by cell surfaced sialic acids. Ambient cold temperature, as an abiotic stress, regulates the survival, stability, transmission, and infection of pathogens. However, the effect of cold temperature on the host receptivity to the pathogens has not been fully studied. The expression of several sialyltransferases were also increased by exposure to cold temperature.

On the other hand, the treatment of Lith-Gly, a sialyltransferase inhibitor, blocked the cold-induced expression of sialic acids on surface of BEAS - 2 B cells. Lithospermum erythrorhizon extract inhibits Der p2-induced inflammatory response through alleviation of thymic stromal lymphopoietin, nuclear factor Kappa B, and inflammasome expression in human bronchial epithelial cells.

Lithospermum erythrorhizon LE and Angelica sinensis AS , widely used in several folk medicine for wound, pus discharge and dermatitis for the history of several hundred years in Asian countries. Sarker, Altaf H. Secondhand smoke SHS is a confirmed lung carcinogen that introduces thousands of toxic chemicals into the lungs. SHS contains chemicals that have been implicated in causing oxidative DNA damage in the airway epithelium.

Although DNA repair is considered a key defensive mechanism against various environmental attacks, such as cigarette smoking, the associations of individual repair enzymes with susceptibility to lung cancer are largely unknown. Representative SSS chemical compounds in the medium were analyzed by mass spectrometry. Taken together, our data strongly suggest that decreased repair of oxidative DNA base lesions due to an impaired NEIL2 expression in non-smokers exposed to SSS would lead to accumulation of mutations in genomic DNA of lung cells over time, thus contributing to the onset of SSS-induced lung cancer.

Cigarette smoke CS is a major risk of chronic obstructive pulmonary disease COPD , contributing to airway inflammation. Our previous study revealed that silymarin had an anti-inflammatory effect in CS- exposed mice. In this study, we attempt to further elucidate the molecular mechanisms of silymarin in CS extract CSE -induced inflammation using human bronchial epithelial cells.

We also observed that inhibiting the activity of ERK with specific inhibitor U led to reduced autophagic level, while knockdown of autophagic gene Beclin-1 and Atg5 decreased the levels of ERK and p38 phosphorylation. Silymarin could attenuate inflammatory responses through intervening in the crosstalk between autophagy and ERK MAPK pathway, and might be an ideal agent treating inflammatory pulmonary diseases. China's Xuan Wei County in Yunnan Province have the world's highest incidence of lung cancer in nonsmoking women times higher than the rest of China.

Previous studies showed, this high lung cancer incidence may be associated with the silica particles embedded in the production combustion from the C1 coal. The aim of this study is to separate the silica particles from production combustion from the C1 bituminous coal in Xuan Wei County of Yunnan Province, and study in vitro toxicity of naturally occurring silica particles on BEAS - 2 B.

Nanodiamond internalization in cells and the cell uptake mechanism. Perevedentseva, E. In this work, internalization of nm nanodiamonds by A lung human adenocarcinoma cell , Beas - 2 b non-tumorigenic human bronchial epithelial cell , and HFL-1 fibroblast-like human fetal lung cell is studied and compared.

The penetration of nanodiamond into the cells was observed using confocal fluorescence imaging and Raman imaging methods. Visualization of the nanodiamond in cells allows comparison of the internalization for diamond nanoparticles in cancer A cell , non-cancer HFL-1, and Beas - 2 b cells. The dose-dependent and time-dependent behavior of nanodiamond uptake is observed in both cancer as well as non-cancer cells. The mechanism of nanodiamond uptake by cancer and non-cancer cells is analyzed by blocking different pathways.

The uptake of nanodiamond in both cancer and non-cancer cells was found predominantly via clathrin-dependent endocytosis. In spite of observed similarity in the uptake mechanism for cancer and non-cancer cells , the nanodiamond uptake for cancer cell quantitatively exceeds the uptake for non-cancer cells , for the studied cell lines. The observed difference in internalization of nanodiamond by cancer and non-cancer cells is discussed. Poisson-event-based analysis of cell proliferation.

A protocol for the assessment of cell proliferation dynamics is presented. This is based on the measurement of cell division events and their subsequent analysis using Poisson probability statistics. Detailed analysis of proliferation dynamics in heterogeneous populations requires single cell resolution within a time series analysis and so is technically demanding to implement.

Here, we show that by focusing on the events during which cells undergo division rather than directly on the cells themselves a simplified image acquisition and analysis protocol can be followed, which maintains single cell resolution and reports on the key metrics of cell proliferation.

The technique is demonstrated using a microscope with 1. Analysis of the statistics of the interevent times i. Grain dust induces IL-8 production from bronchial epithelial cells : effect on neutrophil recruitment. There have been several investigations suggesting an involvement of activated neutrophils in the development of grain dust GD -induced occupational asthma. Interleukin-8 in the sputa from GD-induced asthmatic patients increased significantly after the exposure to GD.

To confirm IL-8 production from bronchial epithelial cells when exposed to GD, and to evaluate the role of IL-8 on neutrophil recruitment. We cultured Beas - 2 B , a bronchial epithelial cell line. The level of released IL-8 in the supernatant was measured by enzyme-linked immunosorbent assay. Neutrophil chemotactic activity of the culture supernatant was determined by modified Boyden chamber method.

Interleukin-8 production and neutrophil chemotactic activity from bronchial epithelial cells significantly increased with additions of GD in a dose-dependent manner P cells may be a major cytokine, which induces neutrophil migration into the airways when exposed to GD. The molecular mechanisms of Cr VI carcinogenesis appear to be complex and are poorly defined.

We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr VI treatments in a dose- and time-dependent fashion in BEAS - 2 B lung epithelial cells. The inhibition also occurs in A lung bronchial carcinoma cells. Benzo[a]pyrene BaP , a well-known environmental carcinogen, promotes oxidative stress and DNA damage.

Curcumin and vitamin E VE have potent antioxidative activity that protects cells from oxidative stress and cellular damage. The objectives of the present study were to investigate the adverse effects of BaP on normal human lung epithelial cells BEAS - 2 B , the potential protective effects of curcumin and VE against BaP-induced cellular damage, and the molecular mechanisms of action.

Moreover, the level of activated p53 and PARP-1 were significantly induced by BaP, whereas this induction was markedly reduced after curcumin and VE co-treatment. Survivin was significantly down-regulated by BaP, and curcumin significantly restored survivin expression in BaP- exposed cells.

Curcumin and VE could reverse some of these BaP-mediated alterations and therefore be effective natural compounds against the adverse effects of BaP in lung cells. Plasmacytoid dendritic cells pDCs belong to the family of dendritic cells and possess specific features that distinguish them from conventional dendritic cells.

For instance, pDC are the main interferon-alpha-secreting cells. Plasmacytoid dendritic cells exert both proinflammatory and regulatory functions. This is attested by the involvement of pDC through interferon-alpha secretion in several autoimmune diseases, and by the implication of pDC in tolerance. Here, we discuss the factors that may influence this polarization.

Arsenic exposure induces the Warburg effect in cultured human cells. Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis.

A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases. Following an initial observation that arsenite- exposed cells in culture acidify their media more rapidly than control cells , the report here shows that low level exposure to arsenite 75 ppb is sufficient to induce aerobic glycolysis the Warburg effect as a generalized phenomenon in cultured human primary cells and cell lines.

Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1A. Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases. Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer.

Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD increased liver tumors and promoted lung metaplasia in females. We recently reported that depletion of this protein promotes lung epithelial cell transformation induced by hexavalent chromium [Cr VI ].

However, the early molecular events that mediate this process are not clear. Our data reveal 83 differentially expressed genes. Up-regulation of some neuro-specific genes is also evident, particularly ubiquitin carboxyl-terminal hydrolase L1 UCHL1 , a deubiquitinase and potential biomarker for lung cancer.

Gene 33 deletion also significantly reduced cell proliferation. Interestingly, Cr VI exposure eliminated the difference in cell proliferation between the two genotypes. Gene 33 deletion also significantly elevated cell migration. Our data indicate that combined Gene 33 deletion and chronic Cr VI exposure produces a gene expression pattern and a phenotype resemble those of the transformed lung epithelial cells. Given the known association of UCHL1 with lung cancer, we propose that UCHL1 is an important player in the early stage of lung epithelial cell transformation and tumorigenesis.

The efficiency of photovoltaic cells exposed to pulsed laser light. Future space missions may use laser power beaming systems with a free electron laser FEL to transmit light to a photovoltaic array receiver. The induction pulse format was simulated with an watt average power copper vapor laser and the RF format with a frequency-doubled mode-locked Nd:YAG laser. Averaged current vs bias voltage measurements for each cell were taken at various optical power levels and the efficiency measured at the maximum power point.

Experimental results show that the conversion efficiency for the cells tested is highly dependent on cell minority carrier lifetime, the width and frequency of the pulses, load impedance, and the average incident power.

Three main effects were found to decrease the efficiency of solar cells exposed to simulated FEL illumination: cell series resistance, LC 'ringing', and output inductance. Improvements in efficiency were achieved by modifying the frequency response of the cell to match the spectral energy content of the laser pulse with external passive components.

Xianyu decoction attenuates the inflammatory response of human lung bronchial epithelial cell. Xianyu decoction XD , a Chinese experience recipe, shows inhibitory effects on lung cancer. However, the potential functions of XD on pneumonia were unknown. This study aimed to investigate the effect of XD on inflammatory response of childhood pneumonia. High expression of miRa was observed in serum and cell model of pneumonia.

XD treatment downregulated the level of miRa in pneumonia children. XD downregulated the level of miRa in serum of pneumonia children. Suppressive effects of formoterol and salmeterol on eotaxin-1 in bronchial epithelial cells. Eotaxin-1 CCL11 , an eosinophil-specific C-C chemokine, is a potent chemoattractant for mobilization of eosinophils into airways after allergic stimulation. Eotaxin-1 recruits eosinophils into inflammatory sites, and may play a role in the pathogenesis of asthma.

Formoterol and salmeterol are two inhaled long acting beta 2 adrenoceptor agonists LABAs , widely used for the local treatment of asthma. However, little is known about their effects on the eotaxin-1 expression of bronchial epithelial cells. Effects of formoterol and salmeterol on nuclear and cytosolic pSTAT-6 expression were evaluated by Western blot and immunofluorescence study.

A specific beta 2 adrenoceptor antagonist ICI , reversed their suppression of eotaxin-1 production. Forskolin, an cAMP activator, could also suppress the expression of eotaxin-1 by IL-4 in a dose dependent manner 10 -7 m.

The western blot and immunofluorescence studies demonstrated that formoterol 10 -7 m suppressed the nuclear expression of pSTAT Formoterol and salmeterol, two inhaled long-acting beta 2 agonists, down-regulated IL induced eotaxin-1 expression in BEAS - 2 B cells. The effect was mediated via the beta 2 adrenoceptor, and cAMP.

Formoterol significantly down-regulated pSTAT6 at higher concentration, and further turned off the IL-4 signaling pathway. Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells following exposure to silver nitrate.

Silver Ag possesses antibacterial activity and has been used in wound dressings and deodorant powders worldwide. However, the metabolic behavior and biological roles of Ag in mammals have not been well characterized. In the present study, we exposed human bronchial epithelial cells BEAS - 2 B to AgNO3 and investigated uptake and intracellular distribution of Ag, expression of metallothionein MT , generation of reactive oxygen species ROS , and changes in mitochondrial respiration.

The culture medium concentration of Ag decreased with time and stabilized at 12h. The concentration of both Ag and MT in the soluble cellular fraction increased up to 3h and then decreased, indicating that cytosolic Ag relocated to the insoluble fraction of the cells. The intensity of fluorescence derived from ROS was elevated in the mitochondrial region at 24h.

Ag decreased mitochondrial oxygen consumption in a dose-dependent manner and the activity of mitochondrial complex I-IV enzymes was significantly inhibited following exposure to Ag. In a separate experiment, we found that hydrogen peroxide H2O2 at concentrations as low as 0. These results suggest MT was decomposed by cytosolic H2O2, and then Ag released from MT relocated to insoluble cellular fractions and inhibited electron chain transfer of mitochondrial complexes, which eventually led to cell damage.

Malondialdehyde-acetaldehyde MAA adducted proteins bind to scavenger receptor A in airway epithelial cells. Co-exposure to cigarette smoke and ethanol generates malondialdehyde and acetaldehyde, which can subsequently lead to the formation of aldehyde-adducted proteins. We have previously shown that exposure of bronchial epithelial cells to malondialdehyde-acetaldehyde MAA adducted protein increases protein kinase C PKC activity and proinflammatory cytokine release.

A specific ligand to scavenger receptor A SRA , fucoidan, blocks this effect. Specific cell surface membrane dye co-localized with upregulated SRA after exposure to MAA for min and subsided by 20 min. These data demonstrate that aldehyde-adducted proteins in the lungs rapidly bind to SRA and internalize this receptor prior to the MAA-adducted protein stimulation of PKC-dependent inflammatory cytokine release in airway epithelium.

Berger, John P. Specific cell surface membrane dye co-localized with upregulated SRA after exposure to MAA for 3—7 min and subsided by 20 min. Overexpression of HO-1 assisted PM2. During these episodes, a surge in hospital visits for acute respiratory symptoms and respiratory diseases exacerbation has been reported to be associated with acute exposure to high-levels of particulate matters.

To investigate cell fate determination and the underlying pathogenic mechanisms during severe haze episodes or smog events, we exposed human lung epithelial cells BEAS - 2 B to PM2. Exposure to PM2. In contrast to necrosis, PM2. In conclusion, our results demonstrate that acute exposure to high PM2. Further, this study reveals dual roles for HO-1 in PM2. Sodium metavanadate exhibits carcinogenic tendencies in vitro in immortalized human bronchial epithelial cells.

Pentavalent vanadium compounds induce intracellular changes in vitro that are consistent with those of other carcinogenic substances. While there is no clear evidence that vanadium compounds cause cancer in humans, vanadium pentoxide causes lung cancer in rodents after long-term inhalation exposures and in turn IARC has categorized it as a group 2B possible human carcinogen. The goal of this study was to investigate the carcinogenicity of NaVO3 in the human immortalized bronchial epithelial cell line, Beas - 2 B.

A dose-dependent increase in the number of colonies was observed. In scratch tests, NaVO3-transformed clones could repair a wound faster than controls. DEG from this experiment were compared with the DEG of 5 week NaVO3 exposure with or without recovery, all with adjusted p-values cells , and the recovered cells. The data from this study imply that chronic exposure to NaVO3 causes changes that are consistent with cellular transformation including anchorage-independent growth, enhanced migration ability, and gene expression changes that were likely epigenetically inherited.

Synthesis of protein in intestinal cells exposed to cholera toxin. The mechanism by which cyclic adenosine monophosphate AMP , formed by intestinal epithelial cells in response to cholera toxin, ultimately results in alterations in water and electrolyte transport is poorly understood. Several studies have indicated that inhibitors of transcription or translation block much of the transport of ions and water in the intestine and edema formation in tissue elicited by cholera toxin.

Data presented in this study confirmed the inhibitory effects of cycloheximide on cholera toxin-induced fluid accumulation in the rabbit intestinal loop model. Most of the new protein synthesized in response to cholera toxin was membrane associated and of high molecular weight. The possible significance of the toxin-induced protein relative to cholera pathogenesis was discussed. Exposure to environmental allergens is a major risk factor for asthma development.

Allergens possess proteolytic activity that is capable of disrupting the airway epithelium. Although there is increasing evidence pointing to asthma as an epithelial disease, the underlying mechanism that drives asthma has not been fully elucidated. In this study, we investigated the direct DNA damage potential of aeroallergens on human bronchial epithelial cells and elucidated the mechanisms mediating the damage.

HDM stimulated cellular reactive oxygen species production, increased mitochondrial oxidative stress, and promoted nitrosative stress. Notably, expression of nuclear factor erythroid 2-related factor 2-dependent antioxidant genes was reduced immediately after HDM exposure, suggesting that HDM altered antioxidant responses.

HDM exposure also reduced cell proliferation and induced cell death. Importantly, HDM-induced DNA damage can be prevented by the antioxidants glutathione and catalase, suggesting that HDM-induced reactive oxygen and nitrogen species can be neutralized by antioxidants. Our results show that direct exposure of bronchial epithelial cells to HDM leads to the production of reactive oxygen and nitrogen species that damage DNA and induce cytotoxicity. Necrosis in human neuronal cells exposed to paraquat.

Paraquat PQ is an herbicide that was once used worldwide, but is now prohibited in many nations due to its high toxicity to humans. However, there are still rare cases of the fetal intoxication of PQ, which was purchased prior to the prohibition in Japan. In this study, several cell death pathways, the mitochondrial stress response, and autophagy were examined in SH-SY5Y cells exposed to PQ.

Taken together, our preliminary survey of cellular responses against PQ shows that, although responses of mitochondria and autophagy are observed, subsequent cell death is necrosis. Comparison between micro- and nanosized copper oxide and water soluble copper chloride: interrelationship between intracellular copper concentrations, oxidative stress and DNA damage response in human lung cells.

Nano- and microscale copper oxide particles CuO NP, CuO MP are applied for manifold purposes, enhancing exposure and thus the potential risk of adverse health effects. Based on the pronounced in vitro cytotoxicity of CuO NP, systematic investigations on the mode of action are required. Cytotoxicity, copper uptake and the impact on the oxidative stress response, cell cycle regulation and apoptosis were further analysed on the functional level.

Uptake studies revealed an intracellular copper overload in the soluble fractions of both cytoplasm and nucleus, reaching up to millimolar concentrations in case of CuO NP and considerably lower levels in case of CuO MP and CuCl 2.

Moreover, CuCl 2 caused copper accumulation in the nucleus only at cytotoxic concentrations. Gene expression analysis in BEAS - 2 B and A cells revealed a strong induction of uptake-related metallothionein genes, oxidative stress-sensitive and pro-inflammatory genes, anti-oxidative defense-associated genes as well as those coding for the cell cycle inhibitor p21 and the pro-apoptotic Noxa and DR5.

Also, cell cycle arrest and apoptosis induction were most distinct for CuO NP. The high cytotoxicity and marked impact on gene expression by CuO NP can be ascribed to the strong intracellular copper ion release, with subsequent. Benzo[a]pyrene B[a]P , the most extensively studied carcinogen in cigarette smoke, has been regarded as a critical mediator of lung cancer.

MAPK pathway disturbances drive alterations in cellular processes, such as differentiation, proliferation, and apoptosis, and the disturbances may also modify the AhR pathway itself. Proteomic analysis of secreted proteins by human bronchial epithelial cells in response to cadmium toxicity. For years, many studies have been conducted to investigate the intracellular response of cells challenged with toxic metal s , yet, the corresponding secretome responses, especially in human lung cells , are largely unexplored.

Here, we provide a secretome analysis of human bronchial epithelial cells BEAS - 2 B treated with cadmium chloride CdCl2 , with the aim of identifying secreted proteins in response to Cd toxicity. Proteins from control and spent media were separated by two-dimensional electrophoresis and visualized by silver staining. Our results unveiled that Cd treatment led to the marked upregulation of molecular chaperones, antioxidant enzymes, enzymes associated with glutathione metabolic process, proteins involved in cellular energy metabolism, as well as tumor-suppressors.

Pretreatment of cells with the thiol antioxidant glutathione before Cd treatment effectively abrogated the secretion of these proteins and prevented cell death. Taken together, our results demonstrate that Cd causes oxidative stress-induced cytotoxicity; and the differentially-secreted protein signatures could be considered as targets for potential use as extracellular biomarkers upon Cd exposure.

KGaA, Weinheim. Although several lines of evidence have established the central role of epithelial-to-mesenchymal-transition EMT in malignant progression of non-small cell lung cancers NSCLCs , the molecular events connecting EMT to malignancy remain poorly understood. Jeffery, Hannah C. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT LI-MAIT and their role in biliary immune surveillance remain unexplored.

MAIT cell activation in response to E. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. Importantly, in response to E. Conclusions Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future.

The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure. Yanagisawa, Satoru; Baker, Jonathan R. SIRT1 silent information regulator 2 homolog 1 is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types.

This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase SOD 2 and 3; therefore seemed to be an adaptive response. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.

Intrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future.

Published by Elsevier B. Multidrug-resistant bacterial infections are being increasingly treated in clinics with polymyxins, a class of antibiotics associated with adverse effects in the kidney, nervous system, or airways of a significant proportion of human and animal patients. Although many of the resistant pathogens display enhanced virulence, a hazard of cytotoxic interactions between polymyxin antibiotics and bacterial virulence factors VFs has not been assessed, to date.

Iron chelators, while ineffective against the polymyxins, could rescue all three. Ultrastructural changes in tracheal epithelial cells exposed to oxygen. Scanning microscopy showed a loss of microvilli after 48 h of exposure. In TEM, nonciliated cells appeared swollen and often encroached on the ciliated cells.

A heavy mucous blanket remained even after processing. Proliferation of human mammary cancer cells exposed to hydroxycholesterol. The aim of the present study was to identify the possible mechanisms by which certain estradiol receptor ER -positive mammary tumor cells remain resistant to treatment with anti-estrogens or inhibitors of local estradiol E2 production. The effects reported herein may be extrapolated to infiltrating mammary cancer, where the activity of local macrophages may stimulate tumor growth.

We suggest that increased breast cancer growth in obese patients may be related to increased 27OHC circulatory levels. The aim of the present study was to identify the possible mechanisms by which certain estradiol receptor ER -positive mammary tumor cells remain resistant to treatment with anti-estrogens or inhibitors of local estradiol E 2 production.

Correlation between dielectric property by dielectrophoretic levitation and growth activity of cells exposed to electric field. The purpose of this study is to develop a system analyzing cell activity by the dielectrophoresis method. In this paper, H3 cells exposed to an alternating current AC electric field or a direct current DC electric field were cultivated, and the influence of damage by the electric field on the growth activity of the cells was examined.

Furthermore, it was found that the adverse effects of the electric field on the cell viability and the growth activity were smaller in the AC electric field than the DC electric field. Inhibition of the interactions between eosinophil cationic protein and airway epithelial cells by traditional Chinese herbs.

The eosinophil cationic protein ECP is cytotoxic to bacteria, viruses, parasites and mammalian cells. Cells are damaged via processes of pore formation, permeability alteration and membrane leaking. Some clinical studies indicate that ECP gathers in the bronchial tract of asthma sufferers, damages bronchial and airway epithelial cells , and leads to in breathing tract inflammation; therefore, prevention of the cytotoxicity caused by ECP may serve as an approach to treat airway inflammation.

To achieve the purpose, reduction of the ECP- cell interactions is rational. In this work, the Chinese herbal combinative network was generated to predict and identify the functional herbs from the pools of prescriptions.

It was useful to select the node herbs and to demonstrate the relative binding ability between ECP and Beas - 2 B cells with or withour herb treatments. Eighty three Chinese herbs and prescriptions were tested and five effective herbs and six prescription candidates were selected. On the basis of effective single-herbal drugs and prescriptions, a combinative network was generated. We found that a single herb, Gan-cao, served as a node connecting five prescriptions.

In addition, Sheng-di-huang, Dang-guei and Mu-tong also appeared in five, four and three kinds of prescriptions, respectively. The extracts of these three herbs indeed effectively inhibited the interactions between ECP and Beas - 2 B cells. According to the Chinese herbal combinative network, eight of the effective herbal extracts showed inhibitory effects for ECP internalizing into Beas - 2 B cells.

The major components of Gang-cao and Sheng-di-huang, glycyrrhizic acid and verbascose, respectively, reduced the binding affinity between ECP and cells effectively. Since these Chinese herbs reduced the binding affinity between ECP and cells and inhibited subsequent ECP entrance into cells , they were potential for mitigating the airway inflammation symptoms.

Additionally, we mentioned a new concept to study the. Electrical characterization of single cells using polysilicon wire ion sensor in an isolation window. Based on this, we used a PSW sensor in combination with a mold-cast polydimethylsiloxane PDMS isolation window to detect the adhesion, apoptosis and extracellular acidification of single normal cells and single cancer cells.

The current flowing through the PSW channel was measured. From the PSW channel current change as a function of time, we determined the cell adhesion time by observing the time required for the current change to saturate, since a stable extracellular ion density was established after the cells were completely adhered to the PSW surface. The apoptosis of cells can also be determined when the channel current change drops to zero.

We found that all the NSCLC cells had a higher channel current change and hence a lower pH value than the normal cells anytime after they were seeded. The corresponding average pH values were 5. Our results show that NSCLC cells have a stronger cell -substrate adhesion and a higher extracellular acidification rate than normal cells. Regulated on activation, normal T expressed and secreted RANTES is a chemokine that attracts eosinophils, mast cells , and basophils toward site of allergic inflammation.

Bronchial epithelial cells are first-line barrier against invasive pathogen and also have immunomodulatory function. Albuterol and fenoterol increased intracellular cAMP levels. Dibutyryl-cAMP conferred the similar effects of albuterol and fenoterol.

Albuterol had no effect on pp65 expression. Hexavalent chromium [Cr VI ] species such as chromates are cytotoxic. Inhalational exposure is a primary concern in many Cr-related industries and their immediate environments, and bronchial epithelial cells are directly exposed to inhaled Cr VI. Chromates are readily taken up by cells and are reduced to reactive Cr species which may also result in the generation of reactive oxygen species ROS.

The thioredoxin Trx system has a key role in the maintenance of cellular thiol redox balance and is essential for cell survival. Cells normally maintain the cytosolic Trx1 and mitochondrial Trx2 thioredoxins largely in the reduced state. Redox western blots were used to assess the redox status of the thioredoxins in normal human bronchial epithelial cells BEAS - 2 B incubated with soluble Na2CrO4 or insoluble ZnCrO4 for different periods of time.

Both chromates caused a dose- and time-dependent oxidation of Trx2 and Trx1. Trx2 was more susceptible in that it could all be converted to the oxidized form, whereas a small amount of reduced Trx1 remained even after prolonged treatment with higher Cr concentrations. Only one of the dithiols, presumably the active site, of Trx1 was oxidized by Cr VI. Cr VI did not cause significant GSH depletion or oxidation indicating that Trx oxidation does not result from a general oxidation of cellular thiols.

It was determined that purified TrxR has pronounced Cr VI reducing activity, so competition for electron flow from TrxR might impair its ability to reduce Trx. The in vitro data also suggested some direct redox interaction between Cr VI and Trx. The ability of Cr VI to cause Trx oxidation in cells could contribute to its cytotoxic effects, and could have important implications for cell survival, redox-sensitive cell signaling, and the cells ' tolerance of other oxidant insults.

Cell damage of hepatoma cells exposed to continuous wave ultrasound. Moreover the mechanical effect might also be involved in inducing cell damage because there was significant mitochondria membrane potential loss and no visible ROS detection when cells were exposed to ultrasound for 30 s.

Immune cell -derived exosomes can increase immunity against tumors. In contrast, tumor-derived exosomes can reduce the immunity and can change the tumor microenvironment to further develop and provide metastasis. These effects take place by an alteration in the innate and adaptive immune cell functions. In this experiment, we studied the natural killer NK cells ' effectiveness on tumor cells after expansion and thereafter incubated it with exosomes.

Moreover, we have studied the NB-derived exosomes on NK cell function. The molecular load of the characterized exosomes by means of nanoparticle-tracking analysis, flow cytometry, scanning electron microscopy, and western blot from NK cells exposed to the NB cell revealed their expression of natural killer cell receptors in addition to CD56, NKG2D, and KIR2DL2 receptors.

These exosomes were used to treat NK cells and thereafter administered to NB tumor cells both in vitro and in vivo. Our results showed some kind of NK cells ' education by the exosomes. This education from NK cells previously exposed to NB cell -derived exosomes caused efficient and greater cytotoxicity against NB tumors, but NB-derived exosomes act as tumor promoters by providing a tumor supporting niche.

Hence, this method of preparing the exosomes has a dramatic effect on activation of anti-NK cells against NB cells. Trans, trans-2,4-decadienal induced cell proliferation via p27 pathway in human bronchial epithelial cells. Lung cancer is the leading cause of cancer deaths worldwide. Epidemiological studies have shown that exposure to cooking oil fumes COF is a risk factor for lung cancer.

Increased cell proliferation is considered as the early stages of lung carcinogenesis. Administration of antioxidants may prevent COF-associated lung carcinogenesis. Melatonin is synthesized in the pineal gland and controls circadian rhythm of peripheral adipose tissue, resulting in changes in body weight. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms of circadian rhythm-mediated proliferation in adipose tissue is still limited.

The circadian amplitudes of brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 Bmal1, P c-Myc P c-Myc and then directly stimulated c-Myc transcription. Moreover, Clock physically interacted with histone deacetylase 3 HDAC3 and formed a complex with c-Myc to promote adipocyte proliferation. Melatonin also attenuated circadian disruption and promoted adipocyte proliferation in chronic jet-lagged mice and obese mice.

Our data reveal a novel mechanism that links circadian rhythm to cell proliferation in adipose tissue. These findings also identify a new potential means for melatonin to prevent and treat sleep deprivation-caused obesity. Calmodulin-mediated activation of Akt regulates survival of c-Myc -overexpressing mouse mammary carcinoma cells. In addition, Akt activation by serum and insulin is also inhibited by W However, only c-Myc -overexpressing mouse mammary carcinoma cells but not normal mouse mammary epithelial cells undergo apoptosis in the presence of the calmodulin antagonist W-7, indicating the vital selective role of calmodulin for survival of these cells.

Pharmacological inhibitors of calmodulin kinase kinase and calmodulin kinases II and III do not inhibit EGF- induced Akt activation, and calmodulin antagonist W-7 does not inhibit phosphotyrosine-associated PI-3 kinase activation. Akt is, however, co-immunoprecipitated with calmodulin in an EGF-dependent manner, which is inhibited by calmodulin antagonist W We conclude that calmodulin may serve a vital regulatory function to direct the localization of Akt to the plasma membrane for its activation by PI-3 kinase.

The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes.

This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity. Tea polyphenols can restrict benzo[a]pyrene- induced lung carcinogenesis by altered expression of passociated genes and H-ras, c-myc and cyclin D1. The modulatory influence of tea polyphenols epigallocatechin gallate, epicatechin gallate and theaflavin on benzo[a]pyrene B[a]P - induced lung carcinogenesis in mice was analyzed using histopathological and molecular parameters.

Progression of lung lesions was restricted at the hyperplastic stage by tea polyphenols. A significant reduction in cellular proliferative index and an increase in apoptotic index were noted in the restricted lung lesions. High expression of H-ras, c-myc , cyclin D1 and p53 genes was seen at the inflammatory stage 9th week and in subsequent premalignant lesions, but down-regulation of H-ras at the hyperplastic stage 17th week.

Expression of bcl-2 was high in hyperplastic lesions, whereas the expression of mdm2 and bcl-xl increased only at the moderately dysplastic stage 36th week. The tea polyphenols inhibited inflammatory response in the lung lesions on the 9th week, when decreased expression of H-ras and c-myc and increased expression of bax were noted. These observations indicate that the tea polyphenols can restrict B[a]P- induced lung carcinogenesis by differential modulation of the expression of p53 and its associated genes such as bax, bcl-2, mdm2, p21 and p27, along with H-ras, c-myc and cyclin D1, at different time points.

Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL cells. Although all-trans retinoic acid ATRA is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment.

Therefore, the development of new drugs or effective combination therapy is urgently needed. This treatment also induced growth arrest at the G1 phase. Driver or passenger effects of augmented c-Myc and Cdc20 in gliomagenesis. Cdc20 and c-Myc are commonly overexpressed in a broad spectrum of cancers, including glioblastoma GBM. Despite this clear association, whether c-Myc and Cdc20 overexpression is a driver or passenger event in gliomagenesis remains unclear.

Both c-Myc and Cdc20 induced the proliferation of primary glial progenitor cells. In contrast, Cdc20 decreased the GBM incidence from We used glial progenitor cells from Ntv-a newborn mice to evaluate the role of c-Myc and Cdc20 in the proliferation and transformation of GBM in vitro and in vivo. These results suggest that the driver or passenger of oncogene signaling is dependent on cellular status.

Inhibition of cell differentiation of c-Myc may be a target for anti-glioma therapy. Romeo, Megan M. The human T-cell leukemia retrovirus type-1 HTLV-1 p30II protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation.

However, the molecular and biochemical events that mediate the cooperation between p30II and c-MYC remain to be completely understood. Moreover, p30II inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress.

Sequential treatment with aurora B inhibitors enhances cisplatin-mediated apoptosis via c-Myc. Platinum compound such as cisplatin is the first-line chemotherapy of choice in most patients with ovarian carcinoma. However, patients with inherent or acquired cisplatin resistance often experience relapse. Therefore, novel therapies are urgently required to treat drug-resistant ovarian carcinoma. Here, we showed that compared to the non-functional traditional simultaneous treatment, sequential combination of Aurora B inhibitors followed by cisplatin synergistically enhanced apoptotic response in cisplatin-resistant OVCAR-8 cells.

This effect was accompanied by the induction of polyploidy in a c-Myc -dependent manner, as c-Myc knockdown reduced the efficacy of the combination by suppressing the expression of Aurora B and impairing cellular response to Aurora B inhibitor, as indicated by the decreased polyploidy and hyperphosphorylation of histone H1. Thus, our report reveals for the first time that sequential treatment of Aurora B inhibitors and cisplatin is essential to inhibit ovarian carcinoma by inducing polyploidy and downregulating c-Myc and that c-Myc is identified as a predictive biomarker to select cells responsive to chemotherapeutical combinations targeting Aurora B.

Collectively, these studies provide novel approaches to overcoming cisplatin chemotherapy resistance in ovarian cancer. Pretreatment of Aurora B inhibitors augment apoptotic effects of cisplatin. The synergy of Aurora B inhibitor with cisplatin is dependent on c-Myc expression.

Distinct nuclear arrangement of active and inactive c-myc genes in control and differentiated colon carcinoma cells. Using sequential RNA-DNA fluorescence in situ hybridization, the nuclear arrangement of both the active and inactive c-myc gene as well as its transcription was investigated in colon cancer HT cells induced to differentiate into enterocytes.

Cytogenetic studies revealed the presence of two chromosomes 8 in HT cells, of which the one containing c-myc gene amplicons was substantially larger and easily distinguished from the normal chromosome. This observation enabled detection of both activity and nuclear localization of c-myc genes in single cells and in individual chromosome territories.

Our experiments demonstrate strikingly specific nuclear and territorial arrangements of active genes as compared with inactive ones: on the periphery of their territories facing to the very central region of the cell nucleus. Nuclear arrangement of c-myc genes and transcripts was conserved during cell differentiation and, therefore, independent of the level of differentiation-specific c-myc gene expression. However, after the induction of differentiation, a more internal territorial location was found for the single copy c-myc gene of normal chromosome 8, while amplicons conserved their territorial topography.

Polyglutamine poly Q disorders, such as Huntington's disease HD and spinocerebellar ataxias, represent a group of neurological disorders which arise due to an atypically expanded poly Q tract in the coding region of the affected gene. Pathogenesis of these disorders inside the cells begins with the assembly of these mutant proteins in the form of insoluble inclusion bodies IBs , which progressively sequester several vital cellular transcription factors and other essential proteins, and finally leads to neuronal dysfunction and apoptosis.

We have shown earlier that targeted upregulation of Drosophila myc dmyc dominantly suppresses the poly Q toxicity in Drosophila. The present study examines the ability of the human c-myc proto-oncogene and also identifies the specific c-Myc isoform which drives the mitigation of poly Q -mediated neurotoxicity, so that it could be further substantiated as a potential drug target. We report for the first time that similar to dmyc, tissue-specific induced expression of human c-myc also suppresses poly Q -mediated neurotoxicity by an analogous mechanism.

Among the three isoforms of c-Myc , the rescue potential was maximally manifested by the full-length c-Myc 2 protein, followed by c-Myc 1, but not by c-Myc S which lacks the transactivation domain. Our study suggests that strategies focussing on the transactivation domain of c-Myc could be a very useful approach to design novel drug molecules against poly Q disorders.

The general mechanism underlying the tumor suppressor activity of the Hippo signaling pathway remains unclear. In this study, we explore the molecular mechanisms connecting the Hippo signaling pathway with glucose metabolism.

The inhibition of lactate production and cellular proliferation induced by shikonin also depends on the Hippo pathway activity. In summary, regulation of glucose metabolism could serve as a new tumor suppressor mechanism orchestrated by the Hippo signaling pathway.

Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc : conditional regulation of c-myc transcription by temperature-sensitive v-abl. Retroviral expression vectors carrying the tyrosine kinase oncogenes abl, fms, src, and trk abrogate the requirements of murine myeloid FDC-P1 cells for interleukin-3 IL Factor-independent clones constitutively express c-myc in the absence of IL-3, whereas in parental cultures c-myc transcription requires the presence of the ligand.

To directly test the effect of a tyrosine kinase oncogene on c-myc expression, retroviral constructs containing three different temperature-sensitive mutants of v-abl were introduced into myeloid ILdependent FDC-P1 and 32D cells.

At the permissive temperature, clones expressing temperature-sensitive abl behaved like wild-type abl-containing cells in their growth properties and expressed c-myc constitutively. Temperature shift experiments demonstrated that both IL-3 abrogation and the regulation of c-myc expression correlated with the presence of functional v-abl.

Induction of c-myc expression by reactivation of temperature-sensitive v-abl mimicked c-myc induction by IL-3 in that it did not require protein synthesis and occurred at the level of transcription, with effects on both initiation and a transcription elongation block. However, v-abl-regulated FDC-P1 cell growth differed from ILregulated growth in that c-fos and junB, which are normally induced by IL-3, were not induced by activation of v-abl.

In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously stage 4s-non-amplified.

In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes. Their transcript levels were analyzed in primary neuroblastomas. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression.

Evaluation of the antitumor effects of c-Myc -Max heterodimerization inhibitor F4 in ovarian cancer cells. Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma.

Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. Our objective was to evaluate the potential effects of small-molecule c-Myc inhibitor, F4, on ovarian carcinoma cells and the underlying mechanisms by which F4 exerts its actions.

Consistently, primary cultures of ovarian cancer treated with F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. The response to F4 was independent the level of c-Myc protein over-expression in primary cultures of ovarian carcinoma.

These novel findings suggest that the growth of ovarian cancer cells is dependent upon c-MYC activity and that targeting c-Myc -Max heterodimerization could be a potential therapeutic strategy for ovarian cancer. The critical targets that mediate the functions of oncogenic c-Myc in colorectal cancer have yet to be fully elucidated.

Moreover, we provide a molecular basis for the synergistic combination of Wnt and mTOR inhibitors in treating colorectal cancer with elevated c-Myc. Cancer Res; 78 12 ; Acidosis is a biochemical hallmark of the tumor microenvironment. Here, we report that acute acidosis decreases c-Myc oncogene expression in U human lymphoma cells.

The level of c-Myc transcripts, but not mRNA or protein stability, contributes to c-Myc protein reduction under acidosis. Acidic pH alone is insufficient to reduce c-Myc expression, as it does not decrease c-Myc in H lung cancer cells expressing very low levels of pH-sensing G protein-coupled receptors GPCRs. Instead, c-Myc is slightly increased by acidosis in H cells, but this increase is completely inhibited by ectopic overexpression of TDAG8.

Collectively, our results identify a novel mechanism of c-Myc regulation by acidosis in the tumor microenvironment and indicate that modulation of TDAG8 and related pH-sensing receptor pathways may be exploited as a new approach to inhibit Myc expression. Both coding exons of the c-myc gene contribute to its posttranscriptional regulation in the quiescent liver and regenerating liver and after protein synthesis inhibition.

In vivo, the steady-state level of c-myc mRNA is mainly controlled by posttranscriptional mechanisms. Using a panel of transgenic mice in which various versions of the human c-myc proto-oncogene were under the control of major histocompatibility complex H-2Kb class I regulatory sequences, we have shown that the 5' and the 3' noncoding sequences are dispensable for obtaining a regulated expression of the transgene in adult quiescent tissues, at the start of liver regeneration, and after inhibition of protein synthesis.

These results indicated that the coding sequences were sufficient to ensure a regulated c-myc expression. In the present study, we have pursued this analysis with transgenes containing one or the other of the two c-myc coding exons either alone or in association with the c-myc 3' untranslated region. We demonstrate that each of the exons contains determinants which control c-myc mRNA expression. Moreover, we show that in the liver, c-myc exon 2 sequences are able to down-regulate an otherwise stable H-2K mRNA when embedded within it and to induce its transient accumulation after cycloheximide treatment and soon after liver ablation.

Finally, the use of transgenes with different coding capacities has allowed us to postulate that the primary mRNA sequence itself and not c-Myc peptides is an important component of c-myc posttranscriptional regulation. Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth. The oncoprotein c-Myc is often overexpressed in cancer cells, and the stability of this protein has major significance in deciding the fate of a cell.

Thus, targeting c-Myc levels is an attractive approach for developing therapeutic agents for cancer treatment. This macrocyclic tetrapeptide also regulated PP2A by reducing the levels of its phosphorylated form which regulates the stability of cellular c-Myc protein. Thus [D-Trp]CJ, represents a new lead compound for the potential development of an effective treatment of prostate cancer. According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women.

The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc. This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. The aim of the present study was to analyse c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process.

DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. The level of gene copy increase was measured using the Scion image software. The amplification of both c-Myc and c-erbB-2 was detected in Only one tumour specimen concomitantly showed increased gene copy number for both studied genes.

Interestingly, besides amplification, gene deletion was also detected The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the result of clonal evolution and selection. Cell Competition is an interaction between cells for existence in heterogeneous cell populations of multicellular organisms.

This phenomenon is involved in initiation and progression of cancer where heterogeneous cell populations compete directly or indirectly for the survival of the fittest based on differential gene expression. In Drosophila, cells having lower dMyc expression are eliminated by cell competition through apoptosis when present in the milieu of cells having higher dMyc expression. Thus, we designed a study to develop c-Myc human homolog dependent in vitro cell competition model of human cancer cells.

Cells with higher c-Myc were transfected with c-myc shRNA to prepare cells with lower c-Myc and then co-cultured with the same type of cells having a higher c-Myc in equal ratio. Cells with lower c-Myc showed a significant decrease in numbers when compared with higher c-Myc cells, suggesting "loser" and "winner" status of cells, respectively. During microscopy, engulfment of loser cells by winner cells was observed with higher expression of JNK in loser cells.

Furthermore, elimination of loser cells was prevented significantly, when co-cultured cells were treated with the JNK apoptosis inhibitor. Above results indicate elimination of loser cells in the presence of winner cells by c-Myc -dependent mechanisms of cell competition in human cancer cells.

This could be an important mechanism in human tumors where normal cells are eliminated by c-Myc -overexpressed tumor cells. Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells. Deciding appropriate therapy for multiple myeloma MM is challenging because of the occurrence of multiple chromosomal changes and the fatal nature of the disease. In the current study, gamabufotalin GBT was isolated from toad venom, and its tumor-specific cytotoxicity was investigated in human MM cells.

Further analysis showed that GBT especially evoked the ubiquitination and degradation of c-Myc protein, thereby globally repressing the expression of c-Myc target genes. An E3 ubiquitin-protein ligase, WWP2, was upregulated following JNK activation and played an important role in c-Myc ubiquitination and degradation through direct protein-protein interaction. Taken together, our study identified the potential of GBT as a promising therapeutic agent in the treatment of MM. Mxi1 is a repressor of the c-Myc promoter and reverses activation by USF.

A second B-HLH-LZ protein, Mxi1, is induced during terminal differentiation, and forms heterodimers with Max that also bind E-boxes but tether the mSin3 transcriptional repressor protein along with histone deacetylase thereby antagonizing Myc-dependent activation.

We show that Mxi1 also antagonizes Myc by a second pathway, repression of transcription from the major c-myc promoter, P2. Thus, induction of Mxi1 in terminally differentiating cells may block Myc function by repressing the c-myc gene P2 promoter, as well as by antagonizing Myc-dependent transactivation through E-boxes. Prostate cancer PCa cell radioresistance causes the failure of radiation therapy RT in localized or locally advanced disease. Radiation was delivered using an x-6 MV photon linear accelerator.

U in vivo activity alone or in combination with irradiation was determined in murine xenografts. The clinically approved compound trametinib used in vitro yielded the same effects as U on growth and C-Myc expression. Notably, U and trametinib induced a drastic down-regulation of BMX, which is known to prevent apoptosis in cancer cells.

We reported c-Myc induction drives cholestatic liver injury and cholangiocarcinoma CCA in mice. We also showed induction of Maf proteins MafG and c-Maf contributed to cholestatic liver injury, whereas S-adenosylmethionine SAMe administration was protective. MAT1A expression fell in hepatocytes and bile duct epithelial cells during chronic cholestasis and in murine and human CCA.

The opposite occurred with c-Myc , MafG and c-Maf expression. The transcription factor c-Myc is an important regulator of cellular proliferation, differentiation and embryogenesis. While c-Myc can inhibit myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that c-Myc does not only inhibits myoblast differentiation but also promotes myoblast proliferation and muscle fibre hypertrophy.

By performing chromatin immunoprecipitation and high-throughput sequencing ChIP-seq , we identified the genome-wide binding profile of c-Myc in skeletal muscle cells. Interestingly, we identified four CAMs that can directly bind to the c-Myc 3' UTR and inhibit c-Myc expression, suggesting that a negative feedback loop exists between c-Myc and its target miRNAs during myoblast differentiation.

Linc and linc are directly regulated by c-Myc , and both lincRNAs are involved in the regulation of myoblast proliferation and differentiation by competing for the binding of muscle differentiation-related miRNAs. Our findings do not only provide a genome-wide overview of the role the c-Myc plays in skeletal muscle cells but also uncover the mechanism of how c-Myc and its target genes regulate myoblast proliferation and differentiation, and muscle fibre hypertrophy.

Machiavelli wrote, in his famous political treatise Il Principe, about disrupting organization by planting seeds of dissension or by eliminating necessary support elements. Tumor cells do exactly that by disrupting the organized architecture of epithelial cell layers during progression from contained benign tumor to full-blown invasive cancer. However, it is still unclear whether tumor cells primarily break free by activating oncogenes powerful enough to cause chaos or by eliminating tumor suppressor genes guarding the order of the epithelial organization.

Studies in Drosophila have exposed genes that encode key regulators of the epithelial apicobasal polarity and which, upon inactivation, cause disorganization of the epithelial layers and promote unscheduled cell proliferation. The screen points out LKB1, which is a causal genetic lesion in Peutz-Jeghers cancer syndrome, a gene mutated in certain sporadic cancers and a human homologue of the fly polarity gene par We review the evidence linking Lkb1 protein to polarity regulation in the scope of our recent results suggesting a coupled role for Lkb1 as an architect of organized acinar structures and a suppressor of oncogenic c-Myc.

We finally present models to explain how Lkb1-dependent formation of epithelial architecture is coupled to suppression of normal and oncogene- induced proliferation. Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc. Erythropoietin Epo stimulation of erythroid cells results in the activation of several kinases and a rapid induction of c-myc expression.

Protein kinase C is necessary for Epo up-regulation of c-myc by promoting elongation at the 3'-end of exon 1. PKCepsilon mediates this signal. We now show that Epo triggers two signaling pathways to c-myc.

LY also had no effect on Epo up-regulation of c-fos. LY blocked transcription of c-myc at exon 1. PD had no effect on transcription from exon 1 but, rather, blocked Epo- induced c-myc elongation at the 3'-end of exon 1. These results identify two Epo signaling pathways to c-myc , one of which is PI3K-dependent operating on transcriptional initiation, whereas the other is mitogen-activated protein kinase-dependent operating on elongation.

Activation of protein kinase C induces nuclear translocation of RFX1 and down-regulates c-myc via an intron 1 X box in undifferentiated leukemia HL cells. The inhibition of Myc synthesis accounted for the drop in Myc protein, because PMA treatment had no effect on Myc turnover. Transfection of HL cells with myc reporter gene constructs showed that the RFX1-binding X box was required for the down-regulation of reporter gene expression by PMA. These findings suggest that nuclear translocation and binding of RFX1 to the X box cause the down-regulation of myc expression, which follows acute PKC activation in undifferentiated HL cells.

Cullin3 E3 ubiquitin ligase ubiquitinates a wide range of substrates through substrate-specific adaptors Bric-a-brac, Tramtrack, and Broad complex BTB domain proteins. These E3 ubiquitin ligase complexes are involved in diverse cellular functions. Our recent study demonstrated that decreased Cullin3 expression induces glioma initiation and correlates with poor prognosis of patients with malignant glioma. However, the substrate recognition mechanism associated with tumorigenesis is not completely understood.

Through yeast two-hybrid screening, we identified potassium channel tetramerization domain-containing 2 KCTD2 as a BTB domain protein that binds to Cullin3. As an underlying mechanism for these KCTD2-mediated phenotypic changes, we demonstrated that KCTD2 interacts with c-Myc , which is a key stem cell factor, and causes c-Myc protein degradation by ubiquitination. As a result, KCTD2 depletion acquires GSC features and affects aerobic glycolysis via expression changes in glycolysis-associated genes through c-Myc protein regulation.

This study describes a novel regulatory mode of c-Myc protein in malignant gliomas and provides a potential framework for glioma therapy by targeting c-Myc function. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice.

Natural killer NK cells are lymphocytes with important anti-tumour functions. However, the mechanisms leading to this metabolic phenotype are unclear. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses.

These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function. The c-myc gene amplification observed in human tumors is likely to represent an activation mechanism aiming at an increased transcription level. In order to evaluate the biological significance of this amplification in the malignant transformation the authors designed an experimental model that could possibly mimic this situation in vitro.

They have constructed a series of plasmids which physically link the human c-myc gene to the bovine papilloma virus type 1 genome BPV1 and therefore should be maintained as amplified episomes upon transformation of rodent cells. Immortal cell lines were established by transfection of the hybrid plasmids carrying either the complete BPV1 genome or the transforming region of the viral genome. The analysis of the established cell lines demonstrates that the transfected plasmids are present not as free copies as anticipated but rather integrated as tandem repeats.

They present data which strongly suggest that the immortalization capacity of the hybrid plasmids reflects the activation of the c-myc gene by the transactivable BPV1 enhancer. Although both the BPV1 early genes and the c-myc gene are actively transcribed, most of the cell lines do not display a transformed phenotype.

Structurally related pentacyclic triterpenoids methyl 2-cyano-3,dioxoolean-1,9-dienoate [bardoxolone-methyl Bar-Me ] and methyl 2-trifluoromethyl-3,dioxoolean-1,dienoate CF3DODA-Me contain 2-cyanoenone and 2-trifluoromethylenone moieties, respectively, in their A-rings and differ in the position of their en-one structures in ring C.

In contrast, both Bar-Me and CF3DODA-Me induce reactive oxygen species in HL and Jurkat leukemia cells, inhibit cell growth, induce apoptosis and differentiation, and decrease expression of specificity proteins Sp 1, 3, and 4, and cMyc , and these effects are significantly attenuated after cotreatment with the antioxidant GSH.

In contrast to solid tumor—derived cells, cMyc and Sp transcriptions are regulated independently and cMyc plays a more predominant role than Sp transcription factors in regulating HL or Jurkat cell proliferation and differentiation compared with that observed in cells derived from solid tumors.

Structurally related pentacyclic triterpenoids methyl 2-cyano-3,dioxoolean-1,9-dienoate [bardoxolone-methyl Bar-Me ] and methyl 2-trifluoromethyl-3,dioxoolean-1,dienoate CF 3 DODA-Me contain 2-cyanoenone and 2-trifluoromethylenone moieties, respectively, in their A-rings and differ in the position of their en-one structures in ring C.

In contrast, both Bar-Me and CF 3 DODA-Me induce reactive oxygen species in HL and Jurkat leukemia cells, inhibit cell growth, induce apoptosis and differentiation, and decrease expression of specificity proteins Sp 1, 3, and 4, and cMyc , and these effects are significantly attenuated after cotreatment with the antioxidant GSH. In contrast to solid tumor-derived cells, cMyc and Sp transcriptions are regulated independently and cMyc plays a more predominant role than Sp transcription factors in regulating HL or Jurkat cell proliferation and differentiation compared with that observed in cells derived from solid tumors.

Since patients with MYCN-amplified neuroblastoma have a poor prognosis, targeting MYCN using small molecule inhibitors could represent a promising therapeutic approach. Our previous work also revealed that MYCN-inhibition leads to mitochondrial dysfunction resulting in accumulation of lipid droplets in neuroblastoma cells.

We also assessed their ability to induce apoptosis, neurite outgrowth and lipid accumulation in neuroblastoma cells. Importantly, G5 and F4 were the most efficient in inducing neuronal differentiation and lipid accumulation in MYCN-amplified neuroblastoma cells.

Together our data demonstrate MYCN-binding properties for a selection of small molecules, and provide functional information that could be of importance for future development of targeted therapies against MYCN-amplified neuroblastoma. To analyse the role of Pasteurella haemolytica Leukotoxin LKT in the mechanism of apoptotic cell death of bovine lymphocytes, we evaluated DNA fragmentation and p53 and c-myc expression. DNA fragmentation was analysed by electrophoresis on Agarose gel.

DNA strand breaks in individual apoptotic cells were also detected by an in situ Terminal deoxy nucleotidyl Transferase TdT. The greatest apoptotic effect was obtained using LKT at a concentration of 0. The results show that p53 and c-myc activation by LKT is correlated with apoptosis of bovine lymphocytes and monocytes.

Our data suggest that LKT may have an important role in the bacterial virulence of Pasteurella haemolytica. Proteomic Characterization of the World Trade Center dust-activated mdig and c-myc signaling circuit linked to multiple myeloma.

Several epidemiological studies suggested an increased incidence rate of multiple myeloma MM among first responders and other individuals who exposed to World Trade Center WTC dust. An increased mdig expression in MM bone marrow was observed, which is associated with the disease progression and prognosis of the MM patients. Taken together, these data suggest that WTC dust may be one of the key etiological factors for those who had been exposed for the development of MM by activating mdig and c-myc signaling circuit linked to the ILJAK-STAT3 pathway essential for the tumorigenesis of the malignant plasma cells.

The dependence of cancer on overexpressed c-MYC and its predisposition for polyploidy represents a double puzzle. We address this conundrum by cross-species transcription analysis of c-MYC interacting genes in polyploid vs. Gene-by-gene transcriptome comparison and principal component analysis indicated that c-MYC interactants are significantly overrepresented among ploidy-associated genes. Protein interaction networks and gene module analysis revealed that the most upregulated genes relate to growth, stress response, proliferation, stemness and unicellularity, as well as to the pathways of cancer supported by MAPK and RAS coordinated pathways.

Metabolic pathway analysis also revealed the EMT-linked features, such as global proteome remodeling, oxidative stress, DNA repair and Warburg-like energy metabolism. Genes associated with apoptosis, immunity, energy demand and tumour suppression were mostly down-regulated. Noteworthy, despite the association between polyploidy and ample features of cancer, polyploidy does not trigger it. Possibly it occurs because normal polyploidy does not go that far in embryonalisation and linked genome destabilisation.

In general, the analysis of polyploid transcriptome explained the evolutionary relation of c-MYC and polyploidy to cancer. Non-transmissible Sendai virus vector encoding c-myc suppressor FBP-interacting repressor for cancer therapy. Antitumor efficacy in a mouse xenograft model was also examined. Thus, FIR expressing vectors are potentially applicable for cancer therapy.

Thus, both the valuable effects and side effects of exogenous FIR stimuli should be tested for future clinical application. HA-FIR suppressed. Carbazole ligands as c-myc G-quadruplex binders. The interactions of c-myc G-quadruplex with three carbazole derivatives were investigated by UV-Vis spectrophotometry, fluorescence, CD spectroscopy, and molecular modeling. The results showed that a combination of carbazole scaffold functionalized with ethyl, triazole and imidazole groups resulted in stabilization of the intramolecular G-quadruplex formed by the DNA sequence derived from the NHE III 1 region of c-myc oncogene Pu Binding to the G-quadruplex Pu22 resulted in the significant increase in fluorescence intensity of complexed ligands All ligands were capable of interacting with G4 DNA with binding stoichiometry indicating that two ligand molecules bind to G-quadruplex with comparable affinity, which agrees with binding model of end-stacking on terminal G-tetrads.

New insights into the molecular signature of these rare cancers. The molecular alterations of pancreatic acinar cell carcinomas ACCs and mixed acinar-neuroendocrine carcinomas MANECs are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known.

Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti- c-myc antibody.

Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. Six cases Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs.

Mechanism of estrogen activation of c-myc oncogene expression. The estrogen receptor complex is a known trans-acting factor that regulates transcription of specific genes through an interaction with a specific estrogen-responsive cis-acting element ERE. In previous studies we have shown that in estrogen-responsive human breast cancer cells estrogen rapidly activates c-myc expression. This activated expression occurs through enhanced transcription and does not require the synthesis of new protein intermediates; therefore, an ERE is present in the human c-myc gene regulatory region.

They were used in transient transfection studies in MCF-7 and HeLa cells co-transfected with an estrogen receptor expression vector. These studies reveal that all constructs containing the P2 promoter region exhibited estrogen-regulated CAT expression and that a bp region upstream and encompassing the P2 TATA box is necessary for this activity. Analysis of this bp region failed to identify a cis-acting element with sequences resembling the consensus ERE; however, co-transfection studies with mutant estrogen receptor expression vectors showed that the DNA-binding domain of the receptor is essential for estrogen-regulated CAT gene expression.

To explain these results we propose a new mechanism of estrogen trans-activation in the c-myc gene promoter. Pre-clinical analysis of changes in intra-cellular biochemistry of glioblastoma multiforme GBM cells due to c-Myc silencing. JQ1 is essentially a Myc inhibitor. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition.

The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc , Bcl-2, and Akt. The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole.

The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future.

Effects of alcohol on c-Myc protein in the brain. Alcoholism is a disorder categorized by significant impairment that is directly related to persistent and extreme use of alcohol. The effects of alcoholism on c-Myc protein expression in the brain have been scarcely studied. This is the first study to investigate the role of different characteristics of alcoholism in c-Myc protein levels in the brain.

We analyzed c-Myc protein in the hypothalamus and amygdala from four different animal models of alcohol abuse. We also observed increases in c-Myc protein exposure in animals that are genetically predisposed to alcohol and methamphetamine abuse. Lastly, c-Myc protein was increased in animals that were acutely exposed to methamphetamine when compared to control treated animals. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Aberrant stabilization of c-Myc contributes to many human cancers.

The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc.

This USP36 regulation of c-Myc occurs in the nucleolus. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. High expression levels of USP36 are found in a subset of human breast and lung cancers. However, it remains elusive how they are regulated in HCC. We investigated the mechanisms of regulation of c-myc , c-fos, and c-jun at the early stages of liver regeneration in mice. We show that the transient increase in steady-state levels of c-myc mRNA at the start of liver regeneration is most probably regulated by posttranscriptional mechanisms.

Although there was a marked increase in c-myc transcriptional initiation shortly after partial hepatectomy, a block in elongation prevented the completion of most transcripts. To gain further information on the mechanism of regulation of c-myc expression during liver regeneration, we used transgenic mice harboring the human c-myc gene driven by the H-2K promoter. In these animals, the murine c-myc responded to the growth stimulus generated by partial hepatectomy, whereas the expression of the transgene was constitutive and did not change in the regenerating liver.

However, the mRNA from both genes increased markedly after cycloheximide injection, suggesting that the regulation of c-myc mRNA abundance in the regenerating liver differs from that occurring after protein synthesis inhibition. Furthermore, we show that in normal mice c-fos and c-jun mRNA levels and transcriptional rates increase within 30 min after partial hepatectomy.

Nevertheless, for both c-fos and c-jun, changes in steady-state mRNA detected after partial hepatectomy were much greater than the transcriptional increase. SIRT1 has been found to function as a Class III deacetylase that affects the acetylation status of histones and other important cellular nonhistone proteins involved in various cellular pathways including stress responses and apoptosis.

The data are representative of three individual experiments. Ashton, Gabrielle H. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.

Protein-protein interaction is an essential biochemical event that mediates various cellular processes including gene expression, intracellular signaling, and intercellular interaction. Understanding such interaction is key to the elucidation of mechanisms of cellular processes in biology and diseases.

Osteosarcoma is the most common primary malignancy in bone. Patients who respond poorly to induction chemotherapy are at higher risk of adverse prognosis. The molecular basis for such poor prognosis remains unclear. Recently, increasing evidence has suggested decreased expression of miRa is observed in a number of cancer types, including human osteosarcoma, and decreased miRa is involved in drug resistance.

However, the underlying molecular mechanisms of decreased miRa on cisplatin chemoresistance in osteosarcoma has not been reported. Osteosarcoma U2OS cells were transfected with miRa mimics for 48 h, then the cells were treated with 3. Using siRNA targeting c-Myc and Bim to examine the relation between miRa, c-Myc and Bim expression exposure to cisplatin on cisplatin- induced apoptosis.

Our data indicated that miRa enhanced the sensitivity to cisplatin by upregulation of c-Myc and Bim pathway. Clinicopathological significance of c-MYC in esophageal squamous cell carcinoma. Esophageal squamous cell carcinoma is one of the most common malignant tumors. The oncogene c-MYC is thought to be important in the initiation, promotion, and therapy resistance of cancer. In this study, we aim to investigate the clinicopathologic roles of c-MYC in esophageal squamous cell carcinoma tissue.

This study is aimed at discovering and analyzing c-MYC expression in a series of human esophageal tissues. A total of 95 esophageal squamous cell carcinoma samples were analyzed by the western blotting and immunohistochemistry techniques. Then, correlation of c-MYC expression with clinicopathological features of esophageal squamous cell carcinoma patients was statistically analyzed. In most esophageal squamous cell carcinoma cases, the c-MYC expression was positive in tumor tissues.

The positive rate of c-MYC expression in tumor tissues was There was a statistical difference among adjacent normal tissues, atypical hyperplasia tissues, and tumor tissues. Overexpression of the c-MYC was detected in The positive rate of c-MYC expression was The positive rate of c-MYC was The c-MYC was. In silico identification of novel ligands for G-quadruplex in the c - MYC promoter. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c - MYC.

Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene. In conclusion, combined virtual screening methods were successfully used for discovery of selective c - MYC promoter G-quadruplex binders with anticancer activity. Id2 leaves the chromatin of the E2F4—pcontrolled c-myc promoter during hepatocyte priming for liver regeneration.

The Id inhibitor of DNA binding or inhibitor of differentiation helix—loop—helix proteins are involved in the regulation of cell growth, differentiation and cancer. The fact that the molecular mechanisms of liver regeneration are not completely understood prompted us to study the fate of Id2 in proliferating liver. Id2 increases in liver regeneration after partial hepatectomy, following the early induction of its gene.

Co-immunoprecipitation shows that Id2 forms a complex with E2F4, p and mSin3A in quiescent liver and all these components are present at the c-myc promoter as shown using ChIP chromatin immunoprecipitation. Moreover, as the G0—G1 transition progresses, Id2 and HDAC again bind the c-myc promoter concomitantly with the repression of this gene.

The time course of c-myc binding to the Id2 promoter, as determined by ChIP assays is compatible with a role of the oncoprotein as a transcriptional inducer of Id2 in liver regeneration. Immunohistochemical analysis shows that Id2 also increases in proliferating hepatocytes after bile duct ligation. In this case, the pattern of Id2 presence in the c-myc promoter parallels that found in regenerating liver.

Our results may suggest a control role for Id2 in hepatocyte priming, through a p dissociation-independent regulation of c-myc. Gliomas are among the most frequent adult primary brain tumors. Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival. However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 RH mutants in both univariate and multivariate analyses.

In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas. A multicolour flow cytometric assay for c-MYC protein in B-cell lymphoma. The relationship between c-MYC protein expression and the presence of a c-MYC gene rearrangement in aggressive and high-grade lymphomas was also assessed.

We have developed a reliable multicolour FCM assay to detect c-MYC expression suitable for clinical laboratories that should be helpful to accurately quantify c-MYC expression in B-cell lymphomas. No commercial use is permitted unless otherwise expressly granted. Metabolic labeling of nascent transcribed mRNA indicated that this was primarily a transcription-mediated event.

These data support a model in which high levels of endogenous c-Myc activity induced early after primary B cell infection directly repress LMP1 transcription. During the latent life cycle, EBV expresses a set of viral oncoproteins and noncoding RNAs with the potential to promote cancer. Critical among these is the viral latent membrane protein LMP1. Prior work suggests that LMP1 is essential for EBV to immortalize B cells, but our recent work indicates that LMP1 is not produced at high levels during the first few weeks after infection.

Here we show that transcription of the LMP1 gene can be negatively regulated by a host transcription factor, c-Myc. Ultimately, understanding the regulation of EBV oncogenes will allow us. Induction of the c-myc protooncogene following antigen binding to hapten-specific B cells.

Considerable controversy has centered on the role that the surface immunoglobulin sIg receptor for antigen plays during the induction of B cell activation. However, the authors have recently demonstrated that antigen binding to such hapten-specific B cells does result in the initiation of the membrane phosphatidylinositol cycle.