Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis*
Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis*
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DOI：
10.1074/jbc.m111.338996
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发表时间：
2012-11
期刊：
影响因子：
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通讯作者：
Yang Yang-Yang;Chenji Wang;Pingzhao Zhang;K. Gao;Dejie Wang;Hongxiu Yu;Ting Zhang;Sirui Jiang;S. Hexige;Zehui Hong;A. Yasui;Jun O. Liu;Haojie Huang;Long Yu
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文献类型：
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作者：
Yang Yang-Yang;Chenji Wang;Pingzhao Zhang;K. Gao;Dejie Wang;Hongxiu Yu;Ting Zhang;Sirui Jiang;S. Hexige;Zehui Hong;A. Yasui;Jun O. Liu;Haojie Huang;Long Yu
背景：PHF 1是一种新型PRC2复合物的组成成分，在H3K27甲基化和Hox基因沉默中起重要作用。结果：PHF1通过保护p53免受MDM2介导的泛素化和降解而稳定p53，促进细胞生长停滞和凋亡。结论：PHF 1是p53信号通路的一个新的调节因子。意义：我们揭示了PHF 1在p53通路调控中的一个新功能。Polycomb族蛋白PHF 1是EED-EZH2·Polycomb抑制复合物2的一个重要组成部分，在H3K27甲基化和Hox基因沉默中发挥重要作用。PHF 1还参与人类细胞中DNA双链断裂的反应，通过与Ku70/Ku80相互作用促进非同源末端连接过程。在这里，我们确定了另一个功能的PHF 1作为一个潜在的p53通路激活剂的途径筛选使用发光报告分析。随后的研究表明，PHF 1在体内和体外都能与p53蛋白直接相互作用，并共定位于细胞核中。PHF1与p53的C-末端调节结构域结合。PHF 1的过表达使p53蛋白水平升高，并延长其周转时间。在正常状态和DNA损伤反应中，PHF 1的敲低降低了p53蛋白水平及其靶基因表达。PHF1在机制上保护p53蛋白免于MDM2介导的泛素化和降解。此外，我们发现，PHF1调节细胞生长停滞和依托泊苷诱导的凋亡，在p53依赖的方式。最后，PHF1的表达显着下调，在人类乳腺癌样品。总之，我们建立PHF1作为一种新的p53通路的正调节。这些数据揭示了PHF1在肿瘤发生和/或肿瘤进展中的潜在作用。
Background: PHF1 is a component of a novel PRC2 complex and plays important roles in H3K27 methylation and Hox gene silencing. Results: PHF1 stabilizes p53 to promote cell growth arrest and apoptosis by protecting p53 from MDM2-mediated ubiquitination and degradation. Conclusion: PHF1 is a novel regulator of p53 pathway. Significance: We unraveled a new function of PHF1 in p53 pathway regulation. Polycomb group protein PHF1 is well known as a component of a novel EED-EZH2·Polycomb repressive complex 2 complex and plays important roles in H3K27 methylation and Hox gene silencing. PHF1 is also involved in the response to DNA double-strand breaks in human cells, promotes nonhomologous end-joining processes through interaction with Ku70/Ku80. Here, we identified another function of PHF1 as a potential p53 pathway activator in a pathway screen using luminescence reporter assay. Subsequent studies showed PHF1 directly interacts with p53 proteins both in vivo and in vitro and co-localized in nucleus. PHF1 binds to the C-terminal regulatory domain of p53. Overexpression of PHF1 elevated p53 protein level and prolonged its turnover. Knockdown of PHF1 reduced p53 protein level and its target gene expression both in normal state and DNA damage response. Mechanically, PHF1 protects p53 proteins from MDM2-mediated ubiquitination and degradation. Furthermore, we showed that PHF1 regulates cell growth arrest and etoposide-induced apoptosis in a p53-dependent manner. Finally, PHF1 expression was significantly down-regulated in human breast cancer samples. Taken together, we establish PHF1 as a novel positive regulator of the p53 pathway. These data shed light on the potential roles of PHF1 in tumorigenesis and/or tumor progression.