Mechanisms of p53-dependent apoptosis
Mechanisms of p53-dependent apoptosis
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DOI：
10.1042/0300-5127:0290684
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发表时间：
2001-01-01
影响因子：
3.9
通讯作者：
Green, DR
中科院分区：
文献类型：
--
作者：
Schuler, M;Green, DR
细胞应激，如生长因子剥夺、DNA损伤或癌基因表达，会导致P53投票率抑制蛋白的稳定和激活。根据细胞环境的不同，这会导致两种不同的结果之一：细胞周期停滞或细胞凋亡。通过P53途径诱导的细胞死亡是由caspase蛋白酶执行的，caspase酶通过裂解它们的底物，导致特有的凋亡表型。P53通过线粒体释放细胞色素c和Smac/Diablo等促凋亡因子来激活caspase。释放的细胞色素c可以形成一个高分子量的复合体，即凋亡体，它由适配蛋白Apaf-1和caspase 9组成，在重新聚集到凋亡体后被激活。然后，激活的caspase 9裂解并激活执行死亡程序的效应器caspase，如caspase-3和-7。释放的Smac/Diablo通过抑制IAP caspase抑制蛋白促进caspase激活。线粒体促凋亡因子的释放受促凋亡和抗凋亡的Bcl-2家族蛋白的调控，这些蛋白可以诱导或阻止线粒体外膜的通透性，但P53信号转导Bcl-2家族蛋白的机制尚不清楚。研究表明，一些促凋亡家族成员，如BAX、NOXA或PUMA，是P53的转录靶标。此外，还描述了P53的转录非依赖性、促凋亡活性。阐明P53依赖的途径，导致线粒体外膜通过促凋亡蛋白Bcl2家族通透性，是揭示应激诱导细胞凋亡机制的关键。
Cellular stresses, such as growth factor deprivation, DNA damage or oncogene expression, lead to stabilization and activation of the p53 turnout suppressor protein. Depending on the cellular context, this results in one of two different outcomes: cell cycle arrest or apoptotic cell death. Cell death induced through the p53 pathway is executed by the caspase proteinases, which, by cleaving their substrates, lead to the characteristic apoptotic phenotype. Caspase activation by p53 occurs through the release of apoptogenic factors from the mitochondria, including cytochrome c and Smac/DIABLO. Released cytochrome c allows the formation of a high-molecular weight complex, the apoptosome, which consists of the adapter protein Apaf-1 and caspase 9, which is activated following recruitment into the apoptosome. Active caspase 9 then cleaves and activates the effector caspases, such as caspases-3 and -7, which execute the death program. Released Smac/DIABLO facilitates caspase activation through repression of the IAP caspase inhibitor proteins. The release of mitochondrial apoptogenic factors is regulated by the pro- and anti-apoptotic Bcl-2 family proteins, which either induce or prevent the permeabilization of the outer mitochondrial membrane, The mechanism by which p53 signals to the Bcl-2 family proteins is unclear. It was shown that some of the pro-apoptotic family members, such as Bax, Noxa or PUMA, are transcriptional targets of p53. In addition, transcription-independent, pro-apoptotic activities of p53 have been described. The elucidation of the p53-dependent pathway, resulting in mitochondrial outer membrane permeabilization through the pro-apoptotic Bcl-2 family proteins, is a key to unveiling the mechanism of stress-induced apoptosis.