來自復(fù)旦大學(xué)、東南大學(xué)的研究人員在新研究中揭示了Polycomb group(PcG)蛋白PHF1的一個(gè)新功能,，證實(shí)其參與調(diào)控了p53介導(dǎo)的細(xì)胞生長阻滯和凋亡,，相關(guān)論文發(fā)表在1月4日的《生物化學(xué)期刊》（JBC）上。
領(lǐng)導(dǎo)這一研究的是復(fù)旦大學(xué)生命科學(xué)學(xué)院的余龍（Long Yu）教授,，其主要從事肝癌發(fā)生的分子遺傳學(xué)機(jī)制研究和抗肝癌藥物小分子化合物篩選,、以及重大疾病相關(guān)基因的系統(tǒng)生物學(xué)及藥物開發(fā)研究。
PRC2沉默復(fù)合物是新近發(fā)現(xiàn)的具有組蛋白甲基轉(zhuǎn)移酶活性的多亞基復(fù)合物, 主要通過催化組蛋白3第27位三甲基化(H3K27me3)修飾介導(dǎo)基因沉默, 參與X染色體失活,、細(xì)胞分化和胚胎發(fā)育調(diào)節(jié),。作為PRC2復(fù)合物的重要組成亞基PHF1在H3K27甲基化作用和Hox基因沉默中起著關(guān)鍵的作用。此外,，研究證實(shí)PHF1還參與了人類細(xì)胞DNA雙鏈斷裂反應(yīng),，通過與Ku70/Ku80的互作促進(jìn)了非同源性末端連接過程。
在這篇文章中,，研究人員揭示了PHF1的另一個(gè)功能,，利用熒光報(bào)告分析進(jìn)行信號通路篩查證實(shí)PHF1是一種潛在的p53信號激活子。隨后的體內(nèi)外研究表明PHF1與p53蛋白共定位于細(xì)胞核,，兩者之間發(fā)生了直接的互作,。PHF1結(jié)合到了p53的C末端調(diào)控域。PHF1過表達(dá)可以提高p53蛋白水平,，延長p53蛋白周轉(zhuǎn)（turnover）,。
研究人員證實(shí)抑制PHF1可降低正常狀態(tài)下及DNA損傷反應(yīng)中的p53蛋白水平和靶基因表達(dá)。進(jìn)一步的機(jī)制研究證實(shí)PHF1保護(hù)p53蛋白,，避免了MDM2介導(dǎo)的泛素化和降解,。此外，研究人員還證實(shí)PHF1以一種p53依賴性形式調(diào)控了細(xì)胞生長停滯和依托泊苷（etoposide）誘導(dǎo)的凋亡,。最后,，研究人員證實(shí)在人類乳腺癌樣本中PHF1的表達(dá)顯著下調(diào)。
新研究確定了PHF1是p53信號的一個(gè)新型正調(diào)控因子,。這些研究數(shù)據(jù)揭示了PHF1在腫瘤發(fā)生及進(jìn)程中的潛在作用,。(生物谷Bioon.com)
doi: 10.1074/jbc.M111.338996
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PMID:
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.
