期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 29, 页码 22473-22483出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.081042
关键词
-
资金
- National Institutes of Health [RO1 CA109285, RO1 CA111786]
Multiple mechanisms have been proposed for the mitochondrial function of p53 that are either dependent on or independent of its transcriptional activity. However, none of these mechanisms involves Bim functioning downstream of p53 mitochondrial translocation. Utilizing a p53 nuclear localization signal mutant, whose nuclear import is completely abrogated, we demonstrate that its apoptotic activity at the outer mitochondrial membrane, which involves conformational changes in Bax and Bak, is mediated by Bim. We further demonstrate an inverse correlation between the binding levels of p53 and Bim to Mcl-1. Thus, enhanced binding of p53 to Mcl-1 involves the disruption of existing complexes between Mcl-1 and Bim. We propose that mitochondrial p53 functions as a Bim derepressor by releasing Bim from sequestrating complexes with Mcl-1, Bcl-2, and Bcl-XL, and allowing its engagement in Bak/Bax activation.
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