来自复旦大学、东南大学的研究人员在新研究中揭示了Polycomb group(PcG)蛋白PHF1的一个新功能，证实其参与调控了p53介导的细胞生长阻滞和凋亡，相关论文发表在1月4日的《生物化学杂志》（JBC）上。
领导这一研究的是复旦大学生命科学学院的余龙（Long Yu）教授，其主要从事肝癌发生的分子遗传学机制研究和抗肝癌药物小分子化合物筛选、以及重大疾病相关基因的系统生物学及药物开发研究。
PRC2沉默复合物是新近发现的具有组蛋白甲基转移酶活性的多亚基复合物, 主要通过催化组蛋白3第27位三甲基化(H3K27me3)修饰介导基因沉默, 参与X染色体失活、细胞分化和胚胎发育调节。作为PRC2复合物的重要组成亚基PHF1在H3K27甲基化作用和Hox基因沉默中起着关键的作用。此外，研究证实PHF1还参与了人类细胞DNA双链断裂反应，通过与Ku70/Ku80的互作促进了非同源性末端连接过程。
在这篇文章中，研究人员揭示了PHF1的另一个功能，利用荧光报告分析进行信号通路筛查证实PHF1是一种潜在的p53信号激活子。随后的体内外研究表明PHF1与p53蛋白共定位于细胞核，两者之间发生了直接的互作。PHF1结合到了p53的C末端调控域。PHF1过表达可以提高p53蛋白水平，延长p53蛋白周转（turnover）。
研究人员证实抑制PHF1可降低正常状态下及DNA损伤反应中的p53蛋白水平和靶基因表达。进一步的机制研究证实PHF1保护p53蛋白，避免了MDM2介导的泛素化和降解。此外，研究人员还证实PHF1以一种p53依赖性形式调控了细胞生长停滞和依托泊苷（etoposide）诱导的凋亡。最后，研究人员证实在人类乳腺癌样本中PHF1的表达显着下调。
新研究确定了PHF1是p53信号的一个新型正调控因子。这些研究数据揭示了PHF1在肿瘤发生及进程中的潜在作用。(生物谷Bioon.com)
doi: 10.1074/jbc.M111.338996
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Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis*
Yang Yang‡,1, Chenji Wang‡,1, Pingzhao Zhang‡§,1, Kun Gao‡, Dejie Wang‡, Hongxiu Yu§, Ting Zhang‡, Sirui Jiang‡, Saiyin Hexige‡, Zehui Hong¶, Akira Yasui**, Jun O. Liu‖, Haojie Huang‡‡ and Long Yu‡§,2
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.
