Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway
Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway
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DOI：
10.1038/sj.onc.1205353
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发表时间：
2002-04-18
期刊：
影响因子：
8
通讯作者：
Liu, SX
中科院分区：
文献类型：
--
作者：
Mirza, A;McGuirk, M;Liu, SX
Survivin是一种凋亡抑制蛋白，在大多数肿瘤中过度表达。在许多肿瘤中生存素的异常表达和野生型p53的缺失促使我们研究这两个事件之间可能的联系。在这里，我们表明，野生型p53抑制生存素表达在mRNA和蛋白质水平。瞬时转染分析表明，野生型p53的表达与各种细胞类型中生存素启动子的强烈抑制有关，而突变型p53则不然。外源性生存素蛋白的过度表达以剂量依赖性方式从p53诱导的凋亡中拯救细胞，这表明生存素的缺失至少部分介导了p53依赖性凋亡途径。尽管生存素启动子中存在两个推定的p53结合位点，但缺失和突变分析表明，这两个位点都不是生存素表达的转录抑制所必需的。染色质免疫沉淀试验证实了这一点。进一步的分析表明，在Survivin启动子内的染色质修饰可能是p53沉默Survivin基因转录的分子解释。
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.