Pro-proliferative FoxM1 is a target of p53-mediated repression.
Pro-proliferative FoxM1 is a target of p53-mediated repression.
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DOI：
10.1038/onc.2009.282
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发表时间：
2009-12-03
期刊：
影响因子：
8
通讯作者：
Prives, C.
中科院分区：
文献类型：
--
作者：
Barsotti, A. M.;Prives, C.
p53肿瘤抑制蛋白作为转录因子调节细胞对多种应激的反应。在这项研究中，我们表明，p53是下调FoxM 1所必需的，FoxM 1是一种重要的转录因子，调节许多G2/M特异性基因，并在许多实体瘤中过表达。DNA损伤后，p53促进FoxM 1 mRNA的抑制，这伴随着FoxM 1蛋白水平的降低。在p53表达减少的细胞中，FoxM 1在DNA损伤后上调。Nutlin是一种p53的小分子激活剂，在两种细胞系中抑制FoxM 1水平，其中DNA损伤仅促进轻度抑制。从机制上讲，p53介导的FoxM 1抑制部分依赖于p21和视网膜母细胞瘤（Rb）家族，尽管在某些情况下也观察到p21非依赖性FoxM 1抑制。FoxM 1对细胞命运的重要性通过观察FoxM 1消融后的G2/M停滞来指示。最后，我们的研究结果表明，p53介导的FoxM 1抑制维持一个稳定的G2期阻滞的潜在贡献。
The p53 tumor suppressor protein acts as a transcription factor to modulate cellular responses to a wide variety of stresses. In this study we show that p53 is required for the downregulation of FoxM1, an essential transcription factor that regulates many G2/M-specific genes and is overexpressed in a multitude of solid tumors. After DNA damage, p53 facilitates the repression of FoxM1 mRNA, which is accompanied by a decrease in FoxM1 protein levels. In cells with reduced p53 expression, FoxM1 is upregulated after DNA damage. Nutlin, a small-molecule activator of p53, suppresses FoxM1 levels in two cell lines in which DNA damage facilitates only mild repression. Mechanistically, p53-mediated inhibition of FoxM1 is partially p21 and retinoblastoma (Rb) family dependent, although in some cases p21-independent repression of FoxM1 was also observed. The importance of FoxM1 to cell fate was indicated by the observation that G2/M arrest follows FoxM1 ablation. Finally, our results indicate a potential contribution of p53-mediated repression of FoxM1 for maintenance of a stable G2 arrest.
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