Impact of HIPK2 and posttranslational p53 modification on B[a]P/BPDE induced cell death and senescence

HIPK2 和翻译后 p53 修饰对 B[a]P/BPDE 诱导的细胞死亡和衰老的影响

• 批准号: 470145176
• 负责人: Professor Dr. Markus Christmann
• 金额: --
• 依托单位: Institut für Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/470145176?language=en
• 关键词: Impact; HIPK2; posttranslational; p53; modification

Genotoxic stress causes DNA damage that might lead to the accumulation of mutations and carcinogenesis. To counteract these effects, DNA repair mechanisms have evolved in order to remove or tolerate DNA lesions. Besides DNA repair, additional mechanisms involved in protection against carcinogenesis exist. These are the induction of cell death via apoptosis and necrosis, transient cell cycle arrest providing time for proper repair and the induction of “irreversible” cell cycle arrest in form of senescence. A problem in predicting the outcome of an exposure to genotoxic stress is based on the fact, that all pathways can be activated separately or simultaneously, depending on the amount of stress.In our previous work, we showed that at non-toxic concentrations of the environmental carcinogen benzo(a)pyrene (B[a]P) and its active metabolite benzo(a)pyrene 9,10-diol-7,8-epoxide (BPDE), induces a p53-dependend transcriptional activation of the nucleotide excision repair and a p53/p21-mediated transcriptional repression of mismatch repair and homologous recombination, as well as induction of senescence. Whereas these mechanisms are only observed at non-toxic concentrations, activation of p53 and induction of several p53 dependent pro-apoptotic factors is observed at non-toxic and toxic concentrations. Interestingly, at non-toxic concentrations, p53 mediates survival and senescence, whereas at toxic concentrations it mediates cell death. While the initial activation of the DNA damage response does not differ between toxic and non-toxic concentrations, at later time points toxic concentrations cause a change in the DNA damage response, which now leads to cell death. Overall, these findings suggest the existence of specific thresholds at which the p53-dependent pro-survival signalling turns into pro-death signalling. The main focus of this project is to identify the molecular mechanisms by which the DNA damage response is changed and to elucidate whether the threshold for saturated DNA repair correlates to the threshold representing the switch from pro-survival signalling into pro-death signalling. Thus, we will focus on the role of posttranslational modification of p53 and the role of the protein kinase HIPK2 in the decision between live and death upon B[a]P/BPDE exposure.

基因毒性应激导致DNA损伤，可能导致突变积累和致癌。为了抵消这些影响，DNA修复机制已经进化到可以移除或容忍DNA损伤。除了DNA修复之外，还存在其他机制参与防止致癌。它们是通过凋亡和坏死诱导细胞死亡，短暂的细胞周期阻滞为适当的修复提供时间，以及以衰老形式诱导“不可逆的”细胞周期阻滞。预测暴露于基因毒性应激的结果的一个问题是基于这样一个事实，即所有途径都可以单独或同时被激活，这取决于应激的程度。在我们之前的工作中，我们发现在无毒浓度的环境致癌物苯并(a)芘（B[a]P）及其活性代谢物苯并(a)芘9,10-二醇7,8-环氧化物（BPDE）下，诱导p53依赖的核苷酸切除修复的转录激活和p53/p21介导的错配修复和同源重组的转录抑制，以及诱导衰老。虽然这些机制仅在无毒浓度下观察到，但在无毒和有毒浓度下可以观察到p53的激活和几种p53依赖的促凋亡因子的诱导。有趣的是，在无毒浓度下，p53介导存活和衰老，而在有毒浓度下，它介导细胞死亡。虽然DNA损伤反应的初始激活在有毒浓度和无毒浓度之间没有差异，但在稍后的时间点，有毒浓度会引起DNA损伤反应的变化，从而导致细胞死亡。总的来说，这些发现表明存在特定的阈值，p53依赖性的促生存信号转变为促死亡信号。该项目的主要重点是确定DNA损伤反应改变的分子机制，并阐明饱和DNA修复的阈值是否与代表从促生存信号转换为促死亡信号的阈值相关。因此，我们将重点关注p53的翻译后修饰和蛋白激酶HIPK2在B[a]P/BPDE暴露后的生死决定中的作用。