Leu J I-Ju, Dumont Patrick, Hafey Michael, Murphy Maureen E, George Donna L
Department of Genetics, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
Nat Cell Biol. 2004 May;6(5):443-50. doi: 10.1038/ncb1123. Epub 2004 Apr 11.
The tumour suppressor activity of the p53 protein has been explained by its ability to induce apoptosis in response to a variety of cellular stresses. Thus, understanding the mechanism by which p53 functions in the execution of cell death pathways is of considerable importance in cancer biology. Recent studies have indicated that p53 has a direct signalling role at mitochondria in the induction of apoptosis, although the mechanisms involved are not completely understood. Here we show that, after cell stress, p53 interacts with the pro-apoptotic mitochondrial membrane protein Bak. Interaction of p53 with Bak causes oligomerization of Bak and release of cytochrome c from mitochondria. Notably, we show that formation of the p53-Bak complex coincides with loss of an interaction between Bak and the anti-apoptotic Bcl2-family member Mcl1. These results are consistent with a model in which p53 and Mcl1 have opposing effects on mitochondrial apoptosis by interacting with, and modulating the activity of, the death effector Bak.
p53蛋白的肿瘤抑制活性已通过其在应对多种细胞应激时诱导细胞凋亡的能力得到解释。因此，了解p53在细胞死亡途径执行过程中的作用机制在癌症生物学中具有相当重要的意义。最近的研究表明，p53在线粒体诱导细胞凋亡过程中具有直接的信号传导作用，尽管其中涉及的机制尚未完全明确。在此我们表明，细胞应激后，p53与促凋亡线粒体膜蛋白Bak相互作用。p53与Bak的相互作用导致Bak寡聚化并使细胞色素c从线粒体释放。值得注意的是，我们表明p53 - Bak复合物的形成与Bak和抗凋亡Bcl2家族成员Mcl1之间相互作用的丧失同时发生。这些结果与一个模型一致，即p53和Mcl1通过与死亡效应蛋白Bak相互作用并调节其活性，对线粒体凋亡产生相反的影响。
