BLIMP1 regulates cell growth through repression of p53 transcription
BLIMP1 regulates cell growth through repression of p53 transcription
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DOI：
10.1073/pnas.0605562104
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发表时间：
2007-02-06
影响因子：
11.1
通讯作者：
Chin, Keh-Chuang
中科院分区：
文献类型：
--
作者：
Yan, Junli;Jiang, Jianming;Chin, Keh-Chuang
p53的严格调节对于维持正常细胞生长至关重要。在这里，我们报告说，BLIMP1作用于一个自动调节反馈回路，通过抑制p53转录控制p53活性。p53结合并正向调节BLIMP 1，BLIMP 1编码已知的B细胞转录抑制物。通过siRNA敲低BLIMP1导致人结肠癌细胞的凋亡和生长停滞以及原代人成纤维细胞的细胞周期停滞。有趣的是，在BLIMP1耗尽后，p53 mRNA和蛋白质的水平都显著增加，这伴随着p53靶基因的诱导。重要的是，在HCT 116细胞中由BLIMP1消耗诱导的细胞凋亡在缺乏p53的细胞中或在通过siRNA消耗p53的细胞中大部分被消除。我们进一步证明，BLIMP1结合到p53启动子和抑制p53转录，这提供了一个机制解释的诱导p53反应的细胞中的BLIMP1耗尽。因此，抑制p53转录是内源性BLIMP1的关键功能，并且对于正常细胞生长是必需的。
Tight regulation of p53 is essential for maintaining normal cell growth. Here we report that BLIMP1 acts in an autoregulatory feedback loop that controls p53 activity through repression of p53 transcription. p53 binds to and positively regulates BLIMP1, which encodes for a known B cell transcriptional repressor. Knockdown of BLIMP1 by siRNA results in both apoptosis and growth arrest in human colon cancer cells and cell-cycle arrest in primary human fibroblasts. Interestingly, the levels of both p53 mRNA and protein are substantially increased after BLIMP1 depletion, which is accompanied by the induction of p53 target genes. Importantly, the apoptosis induced by BLIMP1 depletion in HCT116 cells is largely abrogated in cells lacking p53 or in cells depleted in p53 by siRNA. We further demonstrate that BLIMP1 binds to the p53 promoter and represses p53 transcription, and this provides a mechanistic explanation for the induction of p53 response in cells depleted of BLIMP1. Hence, suppression of p53 transcription is a crucial function of endogenous BLIMP1 and is essential for normal cell growth.