Transcriptional inhibition of p21WAF1/CIP1 gene (CDKN1) expression by survivin is at least partially p53-dependent: evidence for survivin acting as a transcription factor or co-factor.
Transcriptional inhibition of p21WAF1/CIP1 gene (CDKN1) expression by survivin is at least partially p53-dependent: evidence for survivin acting as a transcription factor or co-factor.
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DOI：
10.1016/j.bbrc.2012.03.147
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发表时间：
2012-05-04
影响因子：
3.1
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Tang L;Ling X;Liu W;Das GM;Li F
越来越多的证据表明，抗凋亡蛋白生存素在促进癌细胞G1/S转换和增殖中的作用。然而，其潜在机制尚不清楚。此外，尽管p53上调p21 WAF 1/CIP 1在p53介导的细胞G1期阻滞中起重要作用，但尚不清楚存活素是否在p21 WAF 1/CIP 1表达的调节中起作用。在此，我们报道了在p53野生型MCF-7乳腺癌细胞中外源性表达survivin抑制p21 WAF 1/CIP 1蛋白、mRNA和启动子活性的表达，而survivin C84 A突变体和反义不能做到这一点。在p53突变型H1650肺癌细胞系中的共转染实验表明，Survivin中和p53诱导的p21 WAF 1/CIP 1表达和启动子活性。重要的是，使用慢病毒生存素shRNA遗传沉默内源性生存素也增强了p53野生型癌细胞中的内源性p21，表明了澄清的生理相关性。我们进一步证明了p53和生存素都在p21 WAF 1/CIP 1启动子的两个p53结合位点（−2313至−2212; −1452至−1310）上相互作用，并且生存素在癌细胞中与p53发生物理相互作用。总之，我们认为生存素可能作为一个转录因子或辅因子与p21 WAF 1/CIP 1启动子上的p53相互作用，导致至少部分通过中和p53介导的p21基因转录激活来抑制p21 WAF 1/CIP 1表达。
Growing evidence suggests a role for the antiapoptotic protein survivin in promotion of cancer cell G1/S transition and proliferation. However, the underlying mechanism is unclear. Further, although upregulation of p21WAF1/CIP1 by p53 plays an important role in p53-mediated cell G1 arrests in response to various distresses, it is unknown whether survivin plays a role in the regulation of p21WAF1/CIP1 expression. Here, we report that exogenous expression of survivin in p53-wild type MCF-7 breast cancer cells inhibits the expression of p21WAF1/CIP1 protein, mRNA and promoter activity, while the survivin C84A mutant and antisense failed to do so. Cotransfection experiments in the p53 mutant H1650 lung cancer cell line showed that survivin neutralizes p53-induced p21WAF1/CIP1 expression and promoter activity. Importantly, genetically silencing of endogenous survivin using lentiviral survivin shRNA also enhances endogenous p21 in p53 wild type cancer cells, suggesting the physiological relevance of the fining. We further demonstrated that both p53 and survivin interacts on the two p53-binding sites in the p21WAF1/CIP1 promoter (−2313 to −2212; −1452 to −1310), and survivin physically interacts with p53 in cancer cells. Together, we propose that survivin may act as a transcription factor or cofactor to interact with p53 on the p21WAF1/CIP1 promoter leading to the inhibition of p21WAF1/CIP1 expression at least in part by neutralizing p53-mediated transcriptional activation of the p21 gene.
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影响因子：
8
作者：
Li, FZ;Ling, X;Brattain, MG
通讯作者：
Brattain, MG
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Pienta, Kenneth J.
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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