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.

基因毒性应激会导致 DNA 损伤，从而可能导致突变积累和致癌作用，为了抵消这些影响，DNA 修复机制已经进化，以消除或耐受 DNA 损伤，此外还存在其他涉及预防致癌作用的机制。通过细胞凋亡和坏死诱导细胞死亡、为适当修复提供时间的短暂细胞周期停滞以及以衰老形式诱导“不可逆”细胞周期停滞的一个问题是基于预测暴露于基因毒性应激的结果。事实上，所有通路都可以单独或同时激活，具体取决于压力的大小。在我们之前的工作中，我们表明，在无毒浓度的环境致癌物苯并（a）芘（B[a]P）和其活性代谢物苯并(a)芘9,10-二醇-7,8-环氧化物(BPDE)，诱导核苷酸切除修复的p53依赖性转录激活和p53/p21介导的转录激活错配修复和同源重组的转录抑制，以及衰老的诱导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观察到p53的激活和几种p53依赖性促凋亡因子的诱导。暗示，在无毒浓度下，p53 介导细胞存活和衰老，而在有毒浓度下，它介导细胞死亡。虽然有毒浓度和无毒浓度之间 DNA 损伤反应的初始激活没有差异，但稍后激活。总体而言，这些发现表明存在特定阈值，在该阈值下，p53 依赖性促生存信号转变成促死亡信号。该项目的目的是确定 DNA 损伤反应发生变化的分子机制，并阐明饱和 DNA 修复的阈值是否与代表从促生存信号转为促死亡信号的阈值相关。关于 p53 翻译后修饰的作用以及蛋白激酶 HIPK2 在 B[a]P/BPDE 暴露后决定生与死中的作用。