p53 triggers apoptosis in oncogene-expressing fibroblasts by the induction of Noxa and mitochondrial Bax translocation

被引:94
作者
Schuler, M
Maurer, U
Goldstein, JC
Breitenbücher, F
Hoffarth, S
Waterhouse, NJ
Green, DR
机构
[1] Johannes Gutenberg Univ Mainz, Dept Med 3, D-55101 Mainz, Germany
[2] Johannes Gutenberg Univ Mainz, Gene Therapy Lab, D-55101 Mainz, Germany
[3] La Jolla Inst Allergy & Immunol, Div Cellular Immunol, San Diego, CA USA
关键词
apoptosis; p53; Bax; cytochrome c; Noxa;
D O I
10.1038/sj.cdd.4401180
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mechanism of p53-dependent apoptosis is still only partly defined. Using early-passage embryonic fibroblasts (MEF) from wild-type (wt), p53(-/-) and bax(-/-) mice, we observe a p53-dependent translocation of Bax to the mitochondria and a release of mitochondrial Cytochrome c during stress-induced apoptosis. These events proceed independent of zVAD-inhibitable caspase activation, are not prevented by dominant negative FADD (DN-FADD), but are negatively regulated by Mdm-2. Bcl-x(L) expression prevents the release of mitochondrial Cytochrome c and apoptosis, but not Bax translocation. At a single-cell level, enforced expression of p53 is sufficient to induce Bax translocation and Cytochrome c release. Real-time RT-PCR analysis reveals a significant induction of RNA expression of Noxa and Bax in p53(+/+), but not in p53(-/-) MEF. Noxa protein expression becomes detectable prior to Bax translocation, and downregulation of endogenous Noxa by RNA interference protects wt MEF against p53-dependent apoptosis. Hence, in oncogene-expressing MEF p53 induces apoptosis by BH3 protein-dependent caspase activation.
引用
收藏
页码:451 / 460
页数:10
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