Yin Y, Terauchi Y, Solomon G G, Aizawa S, Rangarajan P N, Yazaki Y, Kadowaki T, Barrett J C
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Nature. 1998 Feb 12;391(6668):707-10. doi: 10.1038/35648.
Reactive oxygen species have damaging effects on cellular components and so trigger defensive responses by the cell and even programmed cell death, although the mechanisms by which mammalian cells transmit signals in response to oxidative damage are unknown. We report here that the protein p85, a regulator of the signalling protein phosphatidyl-3-OH kinase (PI(3)K), participates in the cell death process that is induced in response to oxidative stress and that this role of p85 in apoptosis does not involve PI(3)K. We show that disruption of p85 by homologous recombination impairs the cellular apoptotic response to oxidative stress. Because the protein p53 is required for cell death induced by oxidative damage, we examined the relation between p85 and p53. Using a chimaeric p53 fusion protein with the oestrogen receptor (p53ER) to supply p53 (p53 is induced upon binding of p53ER to oestradiol) in a p53-deficient cell line, we found that p85 is upregulated by p53 and that its involvement in p53-mediated apoptosis is independent of PI(3)K. We propose that p85 acts as a signal transducer in the cellular response to oxidative stress, mediating cell death regulated by p53.
活性氧对细胞成分具有破坏作用，从而触发细胞的防御反应甚至程序性细胞死亡，尽管哺乳动物细胞响应氧化损伤而传递信号的机制尚不清楚。我们在此报告，信号蛋白磷脂酰-3-羟基激酶（PI(3)K）的调节因子p85蛋白参与了响应氧化应激诱导的细胞死亡过程，并且p85在细胞凋亡中的这一作用不涉及PI(3)K。我们表明，通过同源重组破坏p85会损害细胞对氧化应激的凋亡反应。由于p53蛋白是氧化损伤诱导的细胞死亡所必需的，我们研究了p85与p53之间的关系。在p53缺陷细胞系中，使用与雌激素受体（p53ER）的嵌合p53融合蛋白来提供p53（p53在p53ER与雌二醇结合时被诱导），我们发现p85被p53上调，并且其参与p53介导的细胞凋亡独立于PI(3)K。我们提出，p85在细胞对氧化应激的反应中充当信号转导器，介导由p53调节的细胞死亡。
