Induction of p21 by p65 in p53 null cells treated with Doxorubicin
Induction of p21 by p65 in p53 null cells treated with Doxorubicin
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DOI：
10.1016/j.bbamcr.2008.01.008
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发表时间：
2008-05-01
影响因子：
5.1
通讯作者：
Lu, Yanjun
中科院分区：
文献类型：
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作者：
Ma, Shenglin;Tang, Juanjuan;Lu, Yanjun
NF κ B B/p65是一种能够保护或促进细胞死亡的转录因子。在这里，我们表明，通过I κ BSR或p65 siRNA敲低p65降低了DOX对HCT 116（p53+/+）细胞的细胞毒性作用，这与p21的诱导增加相关。在以前的工作中，我们证明了p21通过其CDK抑制活性抑制细胞死亡。因此，我们建议，p65活性是需要通过限制p53诱导的p21表达的p53依赖性细胞死亡。在HCT 116（p53-/-）细胞中，由于p21表达水平下降，p65表达下调增强了DOX的细胞毒性作用。我们目前的证据表明，在p53无效的肿瘤细胞与DOX治疗，p65参与诱导p21的表达，直接结合到p21启动子。我们的数据表明，p53和p65限制对方的能力，刺激p21的诱导和这种相互抑制机制是一致的模型，其中两个因素的竞争限制池的p300/CBP辅激活蛋白复合物。这些发现表明p21的表达和通过p65对细胞死亡的抗性之间存在关联，p65是一种新的调节机制，其中p21桥接p53和p65之间的转录串扰。(C)2008 Elsevier B. V.保留所有权利。
NF kappa B/p65 is a transcription factor that can protect or contribute to cell death. Here we show that knockdown of p65 by I kappa BSR or p65 siRNA decreased the cytotoxic effect of DOX on HCT116 (p53+/+) cells, correlating with increased induction of p21. In previous work, we demonstrated that p21 suppressed cell death via its CDK-inhibitory activity. Thus, we propose that the p65 activity is required for p53-dependent cell death through limitation of p53-induced p21 expression. In HCT116 (p53-/-) cells, downregulation of p65 expression enhanced the cytotoxic effect of DOX, due to decreased p21 expression levels. We present evidence that in p53-null tumor cells treated with DOX, p65 was involved in induction of p21 expression by directly binding to the p21 promoter. Our data suggested that both p53 and p65 limited each other's ability to stimulate p21 induction and this mutual repression mechanism was consistent with a model in which both factors were competing for limiting pool of p300/CBP coactivator protein complexes. These findings indicate an association between p21 expression and resistance to cell death through p65, a novel regulatory mechanism in which p21 bridges a transcriptional crosstalk between p53 and p65. (C) 2008 Elsevier B.V. All rights reserved.