2012年8月27日 讯 /生物谷BIOON/ --来自美国南佛罗里达大学莫菲特癌症中心(Moffitt Cancer Center)的研究人员和同事们鉴定出一种新的转录因子，即PHF20，并且阐述了它在维持p53的稳定性和转录中所发挥的作用，其中p53基因允许正常细胞生长和抑制肿瘤产生。他们发现PHF20在调节p53中发挥着之前未知的独特作用。
当p53被激活时，它能够修复DNA损伤，并通过结合到DNA上来清除癌细胞。然而，p53如何维持它的基本水平和它是如何被激活的，却一直是个谜，不过鉴定出转录因子PHF20和理解它与P53之间的相互作用，以及它诱导p53产生、让它保持稳定性并且诱导它转录，这些都提供解答这两个问题的线索。
他们的研究结果刊登在Nature Structural & Molecular Biology期刊上，而且也刊登在Journal of Biological Chemistry期刊上。
莫菲特癌症中心研究员Jin Q. Cheng博士说，“当细胞经历让它倾向于变成癌细胞的变化时，p53被激活以便修复DNA损伤或者清除因受到影响而变成癌细胞的细胞，从而阻止肿瘤产生。通常有大量机制对p53保持强大的监督功能，并允许它被快速激活。不过关于p53的调节机制，人们仍然知之甚少。”
在鉴定出PHF20为一种新的转录因子之后，研究人员着手随后的研究：探究人PHF20的功能和它对p53的影响。他们发现PHF20不仅诱导p53转录，而且也直接与p53相互作用而让它保持稳定。而Akt通过与PHF20相互作用而让它磷酸化从而负调节这些过程。
为了确定PHF20缺乏是否可能调节应激诱导(stress-induced)的p53表达，研究人员敲降(knock down)PHF20。为此，他们证实在PHF20缺乏时，p53表达下降。这些发现表明PHF20作为p53的一种关键性调节物而发挥作用，同时也在蛋白Akt和p53之间建立一种新的关联。
根据Cheng博士的说法，鉴定出PHF20为p53的一种调节物是非常有意义的，这是因为PHF20“同时与其他蛋白和DNA发生多种相互作用”，并且能够让p53保持稳定和诱导它转录。
Cheng博士解释道，“p53调节在允许正常细胞生长和抑制肿瘤中发挥着关键性的作用。然而，还需进一步研究来理解PHF20的肿瘤抑制功能和它是否可能参与人类恶性肿瘤产生。”(生物谷Bioon.com)
本文编译自Researchers and colleagues identify PHF20, a regulator of gene P53
doi: 10.1038/nsmb.2353
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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
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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.
