Regulation of apoptosis by the circadian clock through NF-kappaB signaling.
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ABSTRACT:
SUBMITTER: Lee JH
PROVIDER: S-EPMC3141963 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:NF-kappaB is a key activator of inflammatory and immune responses with important pathological roles in cancer, heart disease, and autoimmune diseases. Transcriptional activity of NF-kappaB is regulated by different posttranslational modifications. Here, we report a novel mechanism of NF-kappaB regulation through lysine monomethylation by SET9 methyltransferase. Set9 specifically methylates p65 at lysine 37. Both TNFalpha and IL-1beta treatments induced methylation of p65. Methylated p65 is restricted to the nucleus and this modification regulates the promoter binding of p65. Moreover, Set9 mediated methylation of p65 is required for the expression of a subset of NF-kappaB target genes in response to TNFalpha stimulation.
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Project description:The circadian clock in mammalian organisms is generated by a transcription-translation feedback loop that controls many biochemical pathways at the cellular level and physiology and behavior at the organismal level. Cryptochrome (Cry) is a key protein in the negative arm of the transcription-translation feedback loop. It has been found that Cry mutation in cells with p53-null genotype increased their sensitivity to apoptosis by genotoxic agents. Here we show that this increased sensitivity is due to up-regulation of the p53 gene family member p73 in response to DNA damage. As a consequence, when tumors arising from oncogenic Ras-transformed p53(-/-) and p53(-/-)Cry1(-/-)Cry2(-/-) cells are treated with the anticancer drug oxaliplatin, p53(-/-) tumors continue to grow whereas p53(-/-)Cry1(-/-)Cry2(-/-) tumors exhibit extensive apoptosis and stop growing. This finding provides a mechanistic foundation for overcoming the resistance of p53-deficient tumor cells to apoptosis induced by DNA-damaging agents and suggests that disruption of cryptochrome function may increase the sensitivity of tumors with p53 mutation to chemotherapy.
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Project description:BackgroundThe NF-kappaB regulatory network controls innate immune response by transducing variety of pathogen-derived and cytokine stimuli into well defined single-cell gene regulatory events.ResultsWe analyze the network by means of the model combining a deterministic description for molecular species with large cellular concentrations with two classes of stochastic switches: cell-surface receptor activation by TNFalpha ligand, and IkappaBalpha and A20 genes activation by NF-kappaB molecules. Both stochastic switches are associated with amplification pathways capable of translating single molecular events into tens of thousands of synthesized or degraded proteins. Here, we show that at a low TNFalpha dose only a fraction of cells are activated, but in these activated cells the amplification mechanisms assure that the amplitude of NF-kappaB nuclear translocation remains above a threshold. Similarly, the lower nuclear NF-kappaB concentration only reduces the probability of gene activation, but does not reduce gene expression of those responding.ConclusionThese two effects provide a particular stochastic robustness in cell regulation, allowing cells to respond differently to the same stimuli, but causing their individual responses to be unequivocal. Both effects are likely to be crucial in the early immune response: Diversity in cell responses causes that the tissue defense is harder to overcome by relatively simple programs coded in viruses and other pathogens. The more focused single-cell responses help cells to choose their individual fates such as apoptosis or proliferation. The model supports the hypothesis that binding of single TNFalpha ligands is sufficient to induce massive NF-kappaB translocation and activation of NF-kappaB dependent genes.
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