2012年8月27日 訊 /生物谷BIOON/ --來(lái)自美國(guó)南佛羅里達(dá)大學(xué)莫菲特癌癥中心(Moffitt Cancer Center)的研究人員和同事們鑒定出一種新的轉(zhuǎn)錄因子,，即PHF20，并且闡述了它在維持p53的穩(wěn)定性和轉(zhuǎn)錄中所發(fā)揮的作用,，其中p53基因允許正常細(xì)胞生長(zhǎng)和抑制腫瘤產(chǎn)生,。他們發(fā)現(xiàn)PHF20在調(diào)節(jié)p53中發(fā)揮著之前未知的獨(dú)特作用。
當(dāng)p53被激活時(shí),，它能夠修復(fù)DNA損傷,，并通過(guò)結(jié)合到DNA上來(lái)清除癌細(xì)胞。然而,，p53如何維持它的基本水平和它是如何被激活的,，卻一直是個(gè)謎，不過(guò)鑒定出轉(zhuǎn)錄因子PHF20和理解它與P53之間的相互作用,，以及它誘導(dǎo)p53產(chǎn)生,、讓它保持穩(wěn)定性并且誘導(dǎo)它轉(zhuǎn)錄，這些都提供解答這兩個(gè)問(wèn)題的線索,。
他們的研究結(jié)果刊登在Nature Structural & Molecular Biology期刊上,，而且也刊登在Journal of Biological Chemistry期刊上。
莫菲特癌癥中心研究員Jin Q. Cheng博士說(shuō),，“當(dāng)細(xì)胞經(jīng)歷讓它傾向于變成癌細(xì)胞的變化時(shí),，p53被激活以便修復(fù)DNA損傷或者清除因受到影響而變成癌細(xì)胞的細(xì)胞，從而阻止腫瘤產(chǎn)生,。通常有大量機(jī)制對(duì)p53保持強(qiáng)大的監(jiān)督功能,，并允許它被快速激活。不過(guò)關(guān)于p53的調(diào)節(jié)機(jī)制,，人們?nèi)匀恢跎佟?rdquo;
在鑒定出PHF20為一種新的轉(zhuǎn)錄因子之后,，研究人員著手隨后的研究：探究人PHF20的功能和它對(duì)p53的影響。他們發(fā)現(xiàn)PHF20不僅誘導(dǎo)p53轉(zhuǎn)錄，而且也直接與p53相互作用而讓它保持穩(wěn)定,。而Akt通過(guò)與PHF20相互作用而讓它磷酸化從而負(fù)調(diào)節(jié)這些過(guò)程,。
為了確定PHF20缺乏是否可能調(diào)節(jié)應(yīng)激誘導(dǎo)(stress-induced)的p53表達(dá),，研究人員敲降(knock down)PHF20,。為此，他們證實(shí)在PHF20缺乏時(shí),，p53表達(dá)下降,。這些發(fā)現(xiàn)表明PHF20作為p53的一種關(guān)鍵性調(diào)節(jié)物而發(fā)揮作用，同時(shí)也在蛋白Akt和p53之間建立一種新的關(guān)聯(lián),。
根據(jù)Cheng博士的說(shuō)法,，鑒定出PHF20為p53的一種調(diào)節(jié)物是非常有意義的，這是因?yàn)镻HF20“同時(shí)與其他蛋白和DNA發(fā)生多種相互作用”,，并且能夠讓p53保持穩(wěn)定和誘導(dǎo)它轉(zhuǎn)錄,。
Cheng博士解釋道，“p53調(diào)節(jié)在允許正常細(xì)胞生長(zhǎng)和抑制腫瘤中發(fā)揮著關(guān)鍵性的作用,。然而,，還需進(jìn)一步研究來(lái)理解PHF20的腫瘤抑制功能和它是否可能參與人類(lèi)惡性腫瘤產(chǎn)生。”(生物谷Bioon.com)
本文編譯自Researchers and colleagues identify PHF20, a regulator of gene P53
doi: 10.1038/nsmb.2353
PMC:
PMID:
PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53
Gaofeng Cui, Sungman Park, Aimee I Badeaux, Donghwa Kim, Joseph Lee, James R Thompson, Fei Yan, Satoshi Kaneko, Zengqiang Yuan, Maria Victoria Botuyan, Mark T Bedford, Jin Q Cheng & Georges Mer
PHF20 is a multidomain protein and subunit of a lysine acetyltransferase complex that acetylates histone H4 and p53 but whose function is unclear. Using biochemical, biophysical and cellular approaches, we determined that PHF20 is a direct regulator of p53. A Tudor domain in PHF20 recognized p53 dimethylated at Lys370 or Lys382 and a homodimeric form of this Tudor domain could associate with the two dimethylated sites on p53 with enhanced affinity, indicating a multivalent interaction. Association with PHF20 promotes stabilization and activation of p53 by diminishing Mdm2-mediated p53 ubiquitylation and degradation. PHF20 contributes to upregulation of p53 in response to DNA damage, and ectopic expression of PHF20 in different cell lines leads to phenotypic changes that are hallmarks of p53 activation. Overall our work establishes that PHF20 functions as an effector of p53 methylation that stabilizes and activates p53.
doi: 10.1074/jbc.M111.333922
PMC:
PMID:
Identification of Akt Interaction Protein PHF20/TZP That Transcriptionally Regulates p53
Sungman Park‡,1, Donghwa Kim‡,1, Han C. Dan‡,1, Huihua Chen‡, Joseph R. Testa§,2 and Jin Q. Cheng
Akt regulates a diverse array of cellular functions, including cell survival, proliferation, differentiation, and metabolism. Although a number of molecules have been identified as upstream regulators and downstream targets of Akt, the mechanisms by which Akt regulates these cellular processes remain elusive. Here, we demonstrate that a novel transcription factor, PHF20/TZP (referring to Tudor and zinc finger domain containing protein), binds to Akt and induces p53 expression at the transcription level. Knockdown of PHF20 significantly reduces p53. PHF20 inhibits cell growth, DNA synthesis, and cell survival. Akt phosphorylates PHF20 at Ser291 in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of PHF20 function. These data indicate that PHF20 is a substrate of Akt and plays a role in Akt cell survival/growth signaling.
