Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway

被引:471
作者
Mirza, A
McGuirk, M
Hockenberry, TN
Wu, Q
Ashar, H
Black, S
Wen, SF
Wang, LQ
Kirschmeier, P
Bishop, WR
Nielsen, LL
Pickett, CB
Liu, SX
机构
[1] Schering Plough Corp, Inst Res, Dept Tumor Biol, Kenilworth, NJ 07033 USA
[2] Canji Inc, San Diego, CA 92121 USA
关键词
survivin; p53; transcription; repression; apoptosis;
D O I
10.1038/sj.onc.1205353
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
Survivin is an inhibitor of apoptosis protein, which is over-expressed in most tumors. Aberrant expression of survivin and loss of wild-type p53 in many tumors prompted us to investigate a possible link between these two events. Here we show that wild-type p53 represses survivin expression at both mRNA and protein levels. Transient transfection analyses revealed that the expression of wild-type p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The over-expression of exogenous survivin protein rescues cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least, in part the p53-dependent apoptotic pathway. In spite of the presence of two putative p53-binding sites in the survivin promoter, deletion and mutation analyses suggested that neither site is required for transcriptional repression of survivin expression. This was confirmed by chromatin immunoprecipitation assays. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.
引用
收藏
页码:2613 / 2622
页数:10
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