Essential contribution of caspase 3 CPP32 to apoptosis and its associated nuclear changes
Essential contribution of caspase 3 CPP32 to apoptosis and its associated nuclear changes
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DOI：
10.1101/gad.12.6.806
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发表时间：
1998-03-15
影响因子：
10.5
通讯作者：
Mak, TW
中科院分区：
文献类型：
--
作者：
Woo, M;Hakem, R;Mak, TW
半胱天冬酶是哺乳动物细胞凋亡机制的基本组成部分，但个体半胱天冬酶的精确贡献是有争议的。CPP32 （caspase 3）是一种典型的caspase，在细胞凋亡过程中被激活。在这项研究中，我们采用了一种综合的方法来研究CPP32在细胞凋亡中的作用，研究对象是缺乏CPP32的小鼠、胚胎干细胞（ES）和小鼠胚胎成纤维细胞（mef）。CPP32（ex3-/-）小鼠的生存能力降低，并且与先前的报道一致，表现出神经元凋亡缺陷和神经功能缺陷。CPP32失活可显著减少多种情况下的细胞凋亡，包括活化诱导的外周T细胞死亡（AICD），以及化疗诱导的致癌转化的CPP32(-/-) mef的凋亡。此外，对CPP32的需求可能显著依赖于刺激：在胚胎干细胞中，CPP32是紫外线照射（而非伽马照射）后有效凋亡所必需的。相反，同样的刺激可以表现出对CPP32的组织特异性依赖：因此，TNF - α处理在CPP32缺陷胸腺细胞中诱导正常水平的凋亡，但在致癌转化的mep中诱导有缺陷的凋亡。最后，在某些情况下，某些凋亡事件需要CPP32，而其他凋亡事件不需要CPP32：经历细胞死亡的CPP32（ex3-/-）细胞类型不能进行染色质浓缩和DNA降解，但显示出凋亡的其他特征。综上所述，这些结果表明CPP32在细胞凋亡事件中是一个重要的组成部分，它明显依赖于系统和刺激。因此，抑制CPP32的药物可能优先破坏特定形式的细胞死亡。
Caspases are fundamental components of the mammalian apoptotic machinery, but the precise contribution of individual caspases is controversial. CPP32 (caspase 3) is a prototypical caspase that becomes activated during apoptosis. In this study, we took a comprehensive approach to examining the role of CPP32 in apoptosis using mice, embryonic stem (ES) cells, and mouse embryonic fibroblasts (MEFs) deficient for CPP32. CPP32(ex3-/-) mice have reduced viability and, consistent with an earlier report, display defective neuronal apoptosis and neurological defects. Inactivation of CPP32 dramatically reduces apoptosis in diverse settings, including activation-induced cell death (AICD) of peripheral T cells, as well as chemotherapy-induced apoptosis of oncogenically transformed CPP32(-/-) MEFs. As well, the requirement for CPP32 can be remarkably stimulus-dependent: In ES cells, CPP32 is necessary for efficient apoptosis following UV-but not gamma-irradiation. Conversely, the same stimulus can show a tissue-specific dependence on CPP32: Hence, TNF alpha treatment induces normal levels of apoptosis in CPP32 deficient thymocytes, but defective apoptosis in oncogenically transformed MEPs. Finally, in some settings, CPP32 is required for certain apoptotic events but not others: Select CPP32(ex3-/-) cell types undergoing cell death are incapable of chromatin condensation and DNA degradation, but display other hallmarks of apoptosis. Together, these results indicate that CPP32 is an essential component in apoptotic events that is remarkably system- and stimulus-dependent. Consequently, drugs that inhibit CPP32 may preferentially disrupt specific forms of cell death.