17 results on '"Zimmer, Andreas David"'
Search Results
2. Effects of inflammatory cytokines and hypoxia on hepatocytes and HCC cell lines: ID: 197
- Author
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Zimmer, Andreas David, Battello, Nadia, Hiller, Karsten, Wegner, Andre, Behrmann, Iris, and Haan, Claude
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- 2015
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3. Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance
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DFG, BMBF and Sino-German Cooperation Project [sponsor], Nwosu, Zeribe Chike, Piorońska, Weronika, Battello, Nadia, Zimmer, Andreas David, Dewidar, Bedair, Han, Mei, Pereira, Sharon, Blagojevic, Biljana, Castven, Darko, Charlestin, Verodia, Holenya, Pavlo, Lochead, Julia, De La Torre, Carolina, Gretz, Norbert, Sajjakulnukit, Peter, Zhang, Li, Ward, Matthew H, Marquardt, Jens U, Pasca di Magliano, Marina, Lyssiotis, Costas A, Sleeman, Jonathan, Wölfl, Stefan, Ebert, Matthias Philip, Meyer, Christoph, Hofmann, Ute, Dooley, Steven, DFG, BMBF and Sino-German Cooperation Project [sponsor], Nwosu, Zeribe Chike, Piorońska, Weronika, Battello, Nadia, Zimmer, Andreas David, Dewidar, Bedair, Han, Mei, Pereira, Sharon, Blagojevic, Biljana, Castven, Darko, Charlestin, Verodia, Holenya, Pavlo, Lochead, Julia, De La Torre, Carolina, Gretz, Norbert, Sajjakulnukit, Peter, Zhang, Li, Ward, Matthew H, Marquardt, Jens U, Pasca di Magliano, Marina, Lyssiotis, Costas A, Sleeman, Jonathan, Wölfl, Stefan, Ebert, Matthias Philip, Meyer, Christoph, Hofmann, Ute, and Dooley, Steven
- Abstract
Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. Methods: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. Findings: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. Interpretation: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients.
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- 2020
4. Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome is caused by de novo mutations in protein kinase D1
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Alter, Svenja, primary, Zimmer, Andreas David, additional, Park, Misun, additional, Gong, Jianli, additional, Caliebe, Almuth, additional, Fölster-Holst, Regina, additional, Torrelo, Antonio, additional, Colmenero, Isabel, additional, Steinberg, Susan F, additional, and Fischer, Judith, additional
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- 2020
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5. Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance
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Nwosu, Zeribe Chike, primary, Piorońska, Weronika, additional, Battello, Nadia, additional, Zimmer, Andreas David, additional, Dewidar, Bedair, additional, Han, Mei, additional, Pereira, Sharon, additional, Blagojevic, Biljana, additional, Castven, Darko, additional, Charlestin, Verodia, additional, Holenya, Pavlo, additional, Lochead, Julia, additional, De La Torre, Carolina, additional, Gretz, Norbert, additional, Sajjakulnukit, Peter, additional, Zhang, Li, additional, Ward, Matthew H., additional, Marquardt, Jens U., additional, di Magliano, Marina Pasca, additional, Lyssiotis, Costas A., additional, Sleeman, Jonathan, additional, Wölfl, Stefan, additional, Ebert, Matthias Philip, additional, Meyer, Christoph, additional, Hofmann, Ute, additional, and Dooley, Steven, additional
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- 2020
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6. Phosphorylation of the pyruvate dehydrogenase complex precedes HIF-1-mediated effects and pyruvate dehydrogenase kinase 1 upregulation during the first hours of hypoxic treatment in hepatocellular carcinoma cells
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Zimmer, Andreas David, Walbrecq, Geoffroy, Kozar, Ines, Behrmann, Iris, and Haan, Claude
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pyruvate dehydrogenase kinase ,pyruvate dehydrogenase complex ,hypoxia metabolism ,macromolecular substances ,radical oxygen species ,Original Research ,glycolytic switch - Abstract
The pyruvate dehydrogenase complex (PDC) is an important gatekeeper enzyme connecting glycolysis to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, it has a strong impact on the glycolytic flux as well as the metabolic phenotype of a cell. PDC activity is regulated via reversible phosphorylation of three serine residues on the pyruvate dehydrogenase (PDH) E1α subunit. Phosphorylation of any of these residues by the PDH kinases (PDKs) leads to a strong decrease in PDC activity. Under hypoxia, the inactivation of the PDC has been described to be dependent on the hypoxia-inducible factor 1 (HIF-1)-induced PDK1 protein upregulation. In this study, we show in two hepatocellular carcinoma cell lines (HepG2 and JHH-4) that, during the adaptation to hypoxia, PDH is already phosphorylated at time points preceding HIF-1-mediated transcriptional events and PDK1 protein upregulation. Using siRNAs and small molecule inhibitor approaches, we show that this inactivation of PDC is independent of HIF-1α expression but that the PDKs need to be expressed and active. Furthermore, we show that reactive oxygen species might be important for the induction of this PDH phosphorylation since it correlates with the appearance of an altered redox state in the mitochondria and is also inducible by H2O2 treatment under normoxic conditions. Overall, these results show that neither HIF-1 expression nor PDK1 upregulation is necessary for the phosphorylation of PDH during the first hours of the adaptation to hypoxia.
- Published
- 2016
7. Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome is caused by de novo mutations in protein kinase D1.
- Author
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Alter, Svenja, Zimmer, Andreas David, Park, Misun, Jianli Gong, Caliebe, Almuth, Fölster-Holst, Regina, Torrelo, Antonio, Colmenero, Isabel, Steinberg, Susan F., and Fischer, Judith
- Abstract
Background We describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Methods We performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins. Results We identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. Conclusion The present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Cyclooxygenase-2 contributes to the selective induction of cell death by the endocannabinoid 2-arachidonoyl glycerol in hepatic stellate cells
- Author
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Siegmund, S. V., Wojtalla, A., Schlosser, M., Schildberg, F. A., Knolle, P. A., Nusing, R. M., Zimmer, Andreas David, Strassburg, C. P., and Singer, M. V.
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Cell death ,Hepatic stellate cells ,Hepatocytes ,Prostaglandin D(2) glycerol ester ,lipids (amino acids, peptides, and proteins) ,2-Arachidonoyl glycerol ,Cyclooxygenase-2 ,Biochemistry, biophysics & molecular biology [F05] [Life sciences] ,Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant] - Abstract
The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular mechanisms of this selective induction of HSC death are still unresolved. Interestingly, the inducible isoform of cyclooxygenase, COX-2, can metabolize 2-AG to pro-apoptotic prostaglandin glycerol esters (PG-GEs). We analyzed the roles of COX-2 and endocannabinoid-derived PG-GEs in the differential susceptibility of primary activated HSCs and hepatocytes toward 2-AG-induced cell death. HSCs displayed significant COX-2 expression in contrast to hepatocytes. Similar to 2-AG, treatment of HSCs with PGD2-GE dose-dependently induced cell death independently from cannabinoid receptors that was accompanied by PARP- and caspase 3-cleavage. In contrast to 2-AG, PGD2-GE failed to induce significant ROS formation in HSCs, and depletion of membrane cholesterol did not rescue HSCs from PGD2-GE-induced apoptosis. These findings indicate differential engagement of initial intracellular signaling pathways by 2-AG and its COX-2-derived metabolite PGD2-GE, but similar final cell death pathways. Other PG-GEs, such as PGE2-or PGF2alpha-GE did not induce apoptosis in HSCs. Primary rat hepatocytes were mainly resistant against 2-AG- and PGD2-GE-induced apoptosis. HSCs, but not hepatocytes were able to metabolize 2-AG to PGD2-GE. As a proof of principle, HSCs from COX-2(-/-) mice lacked PDG2-GE production after 2-AG treatment. Accordingly, COX-2(-/-) HSCs were resistant against 2-AG-induced apoptosis. In conclusion, the divergent expression of COX-2 in HSCs and hepatocytes contributes to the different susceptibility of these cell types towards 2-AG-induced cell death due to the generation of pro-apoptotic PGD2-GE by COX-2 in HSCs. Modulation of COX-2-driven metabolization of 2-AG may provide a novel physiological concept allowing the specific targeting of HSCs in liver fibrosis.
- Published
- 2016
9. CK2 phosphorylation of C/EBPdelta regulates its transcription factor activity
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Schwind, Lisa, Zimmer, Andreas David, Gotz, Claudia, and Montenarh, Mathias
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animal structures ,Casein Kinase II/antagonists & inhibitors/genetics/metabolism ,fungi ,Molecular Sequence Data ,Biochemistry, biophysics & molecular biology [F05] [Life sciences] ,HCT116 Cells ,Protein-protein interaction ,Catalytic Domain ,Protein Kinase Inhibitors/pharmacology ,embryonic structures ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Protein kinase CK2 ,Phosphorylation ,Transcription factor ,CCAAT-Enhancer-Binding Protein-delta/genetics/metabolism ,Transcriptome ,Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant] ,Transcription ,Conserved Sequence - Abstract
Protein kinase CK2 plays an essential role in cell viability in lower and higher eukaryotes. As a global regulator it phosphorylates and thereby regulates a broad array of cellular targets including a large number of transcription factors. Here, we have identified the CCAAT/enhancer binding protein delta (C/EBPdelta) as a new substrate for CK2. Using point mutants of C/EBPdelta the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPdelta. For proper functioning as a transcription factor C/EBPdelta has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPdelta nor its interaction with C/EBPbeta, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPdelta. Moreover, we found that CK2 bound to C/EBPdelta, which might help to target CK2 to the transcriptional machinery where it can phosphorylate other transcription factors or co-activators.
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- 2015
10. Phosphorylation of the PDH complex precedes HIF-1-mediated effects and PDK1 upregulation during the first hours of hypoxic treatment in HCC cells
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Zimmer, Andreas David, Walbrecq, Geoffroy, Kozar, Ines, Behrmann, Iris, Haan, Claude, Zimmer, Andreas David, Walbrecq, Geoffroy, Kozar, Ines, Behrmann, Iris, and Haan, Claude
- Published
- 2016
11. The role of HIF-1 in oncostatin M-dependent metabolic reprogramming of hepatic cells.
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Metabolomics (Hiller Group) [research center], Battello, Nadia, Zimmer, Andreas David, Goebel, Carole, Dong, Xiangyi, Behrmann, Iris, Haan, Claude, Hiller, Karsten, Wegner, Andre, Luxembourg Centre for Systems Biomedicine (LCSB): Metabolomics (Hiller Group) [research center], Battello, Nadia, Zimmer, Andreas David, Goebel, Carole, Dong, Xiangyi, Behrmann, Iris, Haan, Claude, Hiller, Karsten, and Wegner, Andre
- Abstract
BACKGROUND: Hypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver cancer development is promoted by an inflammatory microenvironment. The inflammatory cytokine oncostatin M (OSM) was shown to induce the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) under normoxic conditions in hepatocytes and hepatoma cells. HIF-1 alpha is known to orchestrate the expression of numerous genes, many of which code for metabolic enzymes that play key roles in the adaptation of cellular metabolism to low oxygen tension. RESULTS: Here, we show that OSM-induced upregulation of HIF-1 alpha reprograms cellular metabolism in three clones of the human hepatocyte cell line PH5CH (PH5CH1, PH5CH7, and PH5CH8) towards a hypoxia-like metabolic phenotype but has no significant effect on cellular metabolism of HepG2 and JHH-4 hepatoma cells. Although we observed only minor changes in glucose uptake and lactate secretion in PH5CH8 upon OSM treatment, we identified more pronounced changes in intracellular fluxes based on stable isotope labeling experiments. In particular, glucose oxidation in the tricarboxylic acid (TCA) cycle is reduced through pyruvate dehydrogenase kinase 1 (PDK1)-mediated inhibition of the pyruvate dehydrogenase complex, thereby reducing the oxidative TCA cycle flux. As a result of the impaired mitochondrial glucose and glutamine oxidation, the reductive isocitrate dehydrogenase flux was increased. CONCLUSIONS: We provide evidence that connects the inflammatory mediator OSM to a hypoxia-like metabolic phenotype. In the human hepatocyte cell line PH5CH, OSM-mediated upregulation of HIF-1 alpha and PDK1 can induce hypoxia-like metabolic changes, although to a lesser extent than hypoxia itself. Since PDK1 is overexpressed in several cancers, it might provide a causal link between chronic inflammation and malignant cellular transform
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- 2016
12. Phosphorylation of the PDH complex precedes HIF-1-mediated effects and PDK1 upregulation during the first hours of hypoxic treatment in HCC cells
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Haan, Claude, primary, Walbrecq, Geoffroy, additional, Kozar, Ines, additional, Behrmann, Iris, additional, and Zimmer, Andreas David, additional
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- 2016
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13. The role of HIF-1 in oncostatin M-dependent metabolic reprogramming of hepatic cells
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Battello, Nadia, primary, Zimmer, Andreas David, additional, Goebel, Carole, additional, Dong, Xiangyi, additional, Behrmann, Iris, additional, Haan, Claude, additional, Hiller, Karsten, additional, and Wegner, Andre, additional
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- 2016
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14. ID: 197
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Zimmer, Andreas David, primary, Battello, Nadia, additional, Hiller, Karsten, additional, Wegner, Andre, additional, Behrmann, Iris, additional, and Haan, Claude, additional
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- 2015
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15. Sequence interpretation. Functional annotation of mouse genome sequences.
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Nadeau, J. H., Balling, Rudi, Barsh, G., Beier, D., Brown, S. D., Bucan, M., Camper, S., Carlson, G., Copeland, N., Eppig, J., Fletcher, C., Frankel, W. N., Ganten, D., Goldowitz, D., Goodnow, C., Guenet, J. L., Hicks, G., Hrabe de Angelis, M., Jackson, I., Jacob, H. J., Jenkins, N., Johnson, D., Justice, M., Kay, S., Kingsley, D., Lehrach, H., Magnuson, T., Meisler, M., Poustka, A., Rinchik, E. M., Rossant, J., Russell, L. B., Schimenti, J., Shiroishi, T., Skarnes, W. C., Soriano, P., Stanford, W., Takahashi, J. S., Wurst, W., Zimmer, Andreas David, Nadeau, J. H., Balling, Rudi, Barsh, G., Beier, D., Brown, S. D., Bucan, M., Camper, S., Carlson, G., Copeland, N., Eppig, J., Fletcher, C., Frankel, W. N., Ganten, D., Goldowitz, D., Goodnow, C., Guenet, J. L., Hicks, G., Hrabe de Angelis, M., Jackson, I., Jacob, H. J., Jenkins, N., Johnson, D., Justice, M., Kay, S., Kingsley, D., Lehrach, H., Magnuson, T., Meisler, M., Poustka, A., Rinchik, E. M., Rossant, J., Russell, L. B., Schimenti, J., Shiroishi, T., Skarnes, W. C., Soriano, P., Stanford, W., Takahashi, J. S., Wurst, W., and Zimmer, Andreas David
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- 2001
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16. Genome-wide, large-scale production of mutant mice by ENU mutagenesis.
- Author
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Hrabe de Angelis, M. H., Flaswinkel, H., Fuchs, H., Rathkolb, B., Soewarto, D., Marschall, S., Heffner, S., Pargent, W., Wuensch, K., Jung, M., Reis, A., Richter, T., Alessandrini, F., Jakob, T., Fuchs, E., Kolb, H., Kremmer, E., Schaeble, K., Rollinski, B., Roscher, A., Peters, C., Meitinger, T., Strom, T., Steckler, T., Holsboer, F., Klopstock, T., Gekeler, F., Schindewolf, C., Jung, T., Avraham, K., Behrendt, H., Ring, J., Zimmer, Andreas David, Schughart, K., Pfeffer, K., Wolf, E., Balling, Rudi, Hrabe de Angelis, M. H., Flaswinkel, H., Fuchs, H., Rathkolb, B., Soewarto, D., Marschall, S., Heffner, S., Pargent, W., Wuensch, K., Jung, M., Reis, A., Richter, T., Alessandrini, F., Jakob, T., Fuchs, E., Kolb, H., Kremmer, E., Schaeble, K., Rollinski, B., Roscher, A., Peters, C., Meitinger, T., Strom, T., Steckler, T., Holsboer, F., Klopstock, T., Gekeler, F., Schindewolf, C., Jung, T., Avraham, K., Behrendt, H., Ring, J., Zimmer, Andreas David, Schughart, K., Pfeffer, K., Wolf, E., and Balling, Rudi
- Abstract
In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html).
- Published
- 2000
17. ID: 197: Effects of inflammatory cytokines and hypoxia on hepatocytes and HCC cell lines.
- Author
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Zimmer, Andreas David, Battello, Nadia, Hiller, Karsten, Wegner, Andre, Behrmann, Iris, and Haan, Claude
- Subjects
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LIVER cells , *HYPOXEMIA , *LIVER cancer , *GENOMES , *CYTOKINES - Abstract
Hepatocellular carcinoma (HCC), mostly the result of chronic liver diseases, is ranked as the fifth most common cancer world-wide. To find new treatments, a better understanding of the initiation, the progression and the implication of the cellular metabolism in the development of HCC is needed. Hypoxia and IL6-type cytokines can promote tumour growth, influence cellular metabolism and prevent cancer cells from apoptosis [1] . Furthermore, IL6-type cytokines induce the expression of HIF-1 α , one of the key mediators of the cellular response to hypoxia [2] . Constitutively active STAT3 leads to an increased production of lactate under normoxic conditions. This effect was HIF-1 α -dependent [3] . We investigated the effects of the IL6-type cytokine Oncostatin M (OSM) on hepatocytes and HCC cell lines under normoxia. Quantitative real-time PCR and quantitative WB analysis was performed focusing on the regulation of glycolytic enzymes, many being direct HIF-1 α target genes. Contrary to the HCC lines, in non-neoplastic PH5CH8 hepatocytes an OSM-mediated induction of pyruvate dehydrogenase kinase 1 (PDK1) was found together with an increase in the pyruvate dehydrogenase (PDH) phosphorylation level, indicating that these cells shift to a more glycolytic metabolism. Metabolic analysis is being carried out to validate this finding. We found little OSM effects under normoxia on the induction of glycolytic enzymes (mRNA and protein level). Surprisingly, even hypoxic treatment only affected few genes previously described to be HIF-1 α targets. Funded by the University of Luxembourg Tandem project “Meta-IL6”. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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