Stambolsky P, Weisz L, Shats I, Klein Y, Goldfinger N, Oren M, Rotter V
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Cell Death Differ. 2006 Dec;13(12):2140-9. doi: 10.1038/sj.cdd.4401965. Epub 2006 May 26.
The tumor suppressor p53 plays a pivotal role in suppressing tumorigenesis by inducing genomic stability, cell cycle arrest or apoptosis. AIF is a mitochondrial protein, which, upon translocation to the nucleus, can participate in apoptosis, primarily in a caspase-independent contexts. We now report that AIF gene expression is subject to positive transcriptional regulation by p53. Interestingly, unlike most known p53 target genes, the AIF gene is regulated by basal levels of p53, and activation of p53 by genotoxic stress does not result in a substantial further increase in AIF expression. The AIF gene harbors a p53 responsive element, which is bound by p53 within cells. p53 drives efficient induction of large-scale DNA fragmentation, a hallmark of AIF activity. Importantly, caspase-independent death is compromised in cells lacking functional p53, in line with the known role of AIF in this process. Thus, in addition to its documented effects on caspase-dependent apoptosis, p53 may also sensitize cells to caspase-independent death through positive regulation of AIF expression. Moreover, in the absence of overt apoptotic signals, the constitutive induction of AIF by p53 may underpin a cytoprotective maintenance role, based on the role of AIF in ensuring proper mitochondrial function.
肿瘤抑制因子p53通过诱导基因组稳定性、细胞周期阻滞或凋亡在抑制肿瘤发生过程中发挥关键作用。凋亡诱导因子（AIF）是一种线粒体蛋白，转位至细胞核后，主要在不依赖半胱天冬酶的情况下参与凋亡过程。我们现在报道，AIF基因表达受p53的正向转录调控。有趣的是，与大多数已知的p53靶基因不同，AIF基因受p53基础水平的调控，基因毒性应激激活p53并不会导致AIF表达进一步大幅增加。AIF基因含有一个p53反应元件，在细胞内可与p53结合。p53可有效诱导大规模DNA片段化，这是AIF活性的一个标志。重要的是，在缺乏功能性p53的细胞中，不依赖半胱天冬酶的死亡受到影响，这与AIF在该过程中的已知作用一致。因此，除了其对依赖半胱天冬酶凋亡的已记录作用外，p53还可能通过对AIF表达的正向调控使细胞对不依赖半胱天冬酶的死亡敏感。此外，在没有明显凋亡信号的情况下，基于AIF在确保线粒体正常功能中的作用，p53对AIF的组成性诱导可能支持一种细胞保护维持作用。
