Yin Y, Solomon G, Deng C, Barrett J C
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Mol Carcinog. 1999 Jan;24(1):15-24.
Oxidative stress to mammalian cells causes cellular damage and triggers inducible cellular responses leading to cell death by apoptosis. In this paper, we report that p53 was required for programmed cell death induced by oxidative stress in both mouse and human cells and that p53 transactivation was involved in induction of oxidative cell death. Furthermore, we show that p21 was highly responsive to oxidative stress in a p53-dependent manner and that ectopic expression of p21 could increase cellular susceptibility to oxidative stress in the absence of p53. However, p21 was not required for p53-directed oxidative cell death because mouse embryo fibroblasts MEFs lacking p21(p21-/- MEFs) were still susceptible to oxidative cell death. Interestingly, bax, a cell-death mediator regulated by p53, was overexpressed in p21-/- MEFs that underwent cell death by oxidative stress, suggesting a compensation for loss of p21 that may be responsible for the existence of cell-death responses in p21-knockout mouse fibroblasts. Finally, we provide evidence that the retinoblastoma gene product (Rb) is a negative regulator of p21 and a repressor of the cellular apoptotic process. Because p21 is regulated by p53 positively and by Rb negatively, p21 may be a link between p53 and Rb in determining cell fate after oxidative damage.
哺乳动物细胞受到氧化应激会导致细胞损伤，并引发可诱导的细胞反应，最终通过凋亡导致细胞死亡。在本文中，我们报告称，p53是小鼠和人类细胞中氧化应激诱导程序性细胞死亡所必需的，且p53反式激活参与了氧化诱导的细胞死亡。此外，我们发现p21以p53依赖的方式对氧化应激高度敏感，并且在没有p53的情况下，p21的异位表达可增加细胞对氧化应激的敏感性。然而，p21并非p53介导的氧化细胞死亡所必需，因为缺乏p21的小鼠胚胎成纤维细胞（p21-/- MEFs）仍然对氧化细胞死亡敏感。有趣的是，由p53调节的细胞死亡介质bax在因氧化应激而发生细胞死亡的p21-/- MEFs中过表达，这表明p21缺失的补偿作用可能是p21基因敲除小鼠成纤维细胞中存在细胞死亡反应的原因。最后，我们提供证据表明，视网膜母细胞瘤基因产物（Rb）是p21的负调节因子，也是细胞凋亡过程的抑制因子。由于p21受p53正向调节和Rb负向调节，p21可能是p53与Rb之间在氧化损伤后决定细胞命运的一个连接点。
