Ljungman M, Zhang F, Chen F, Rainbow A J, McKay B C
Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0936, USA.
Oncogene. 1999 Jan 21;18(3):583-92. doi: 10.1038/sj.onc.1202356.
The mechanisms by which the p53 response is triggered following exposure to DNA-damaging agents have not yet been clearly elucidated. We and others have previously suggested that blockage of RNA polymerase II may be the trigger for induction of the p53 response following exposure to ultraviolet light. Here we report on the correlation between inhibition of mRNA synthesis and the induction of p53, p21WAF1 and apoptosis in diploid human fibroblasts treated with either UV light, cisplatin or the RNA synthesis inhibitors actinomycin D, DRB, H7 and alpha-amanitin. Exposure to ionizing radiation or the proteasome inhibitor LLnL, however, induced p53 and p21WAF1 without affecting mRNA synthesis. Importantly, induction of p53 by the RNA synthesis or proteasome inhibitors did not correlate with the induction of DNA strand breaks. Furthermore, cisplatin-induced accumulation of active p53 in repair-deficient XP-A cells occurred despite the lack of DNA strand break induction. Our results suggest that the induction of the p53 response by certain toxic agents is not triggered by DNA strand breaks but rather, may be linked to inhibition of mRNA synthesis either directly by the poisoning of RNA polymerase II or indirectly by the induction of elongation-blocking DNA lesions.
暴露于DNA损伤剂后触发p53反应的机制尚未完全阐明。我们和其他人之前曾提出，RNA聚合酶II的阻滞可能是暴露于紫外线后诱导p53反应的触发因素。在此，我们报告了用紫外线、顺铂或RNA合成抑制剂放线菌素D、DRB、H7和α-鹅膏蕈碱处理的二倍体人成纤维细胞中，mRNA合成抑制与p53、p21WAF1诱导及细胞凋亡之间的相关性。然而，暴露于电离辐射或蛋白酶体抑制剂LLnL会诱导p53和p21WAF1，而不影响mRNA合成。重要的是，RNA合成或蛋白酶体抑制剂诱导的p53与DNA链断裂的诱导无关。此外，尽管缺乏DNA链断裂诱导，顺铂仍会在修复缺陷的XP-A细胞中诱导活性p53的积累。我们的结果表明，某些毒性剂诱导p53反应并非由DNA链断裂触发，而是可能与RNA聚合酶II中毒直接抑制mRNA合成或诱导延伸阻滞性DNA损伤间接抑制mRNA合成有关。
