Regulation of Protein Citrullination through p53/PAD14 Network in DNA Damage Response
Regulation of Protein Citrullination through p53/PAD14 Network in DNA Damage Response
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DOI：
10.1158/0008-5472.can-09-2280
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发表时间：
2009-11-15
期刊：
影响因子：
11.2
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
--
作者：
Tanikawa, Chizu;Ueda, Koji;Matsuda, Koichi
在广泛的细胞应激下，p53被激活并通过转录调节其与细胞凋亡、细胞周期停滞和DNA修复相关的靶基因来抑制恶性转化。然而，其参与蛋白质的翻译后修饰尚未得到很好的表征。在这里，我们报告了p53在瓜氨酸蛋白调节中的新作用。p53通过内含子p53结合位点反式激活肽基精氨酸脱亚胺酶4型（PADI 4）。PADI 4基因编码催化蛋白质中精氨酸残基的瓜氨酸化和p53或PADI 4诱导的蛋白质瓜氨酸化的异位表达的酶。此外，各种蛋白质瓜氨酸化响应DNA损伤，但敲低PADI 4或p53显着抑制其瓜氨酸，表明蛋白质瓜氨酸的调节以p53/PADI 4依赖的方式。我们发现，在生理条件下，PADI 4瓜氨酸化组蛋白伴侣蛋白，核磷蛋白（NPM 1），在精氨酸197残基在体内。PADI 4对NPM 1的瓜氨酸化导致其从核仁易位到核质，而PADI 4不改变突变体NPM 1（R197 K）的定位。此外，PADI 4的异位表达抑制肿瘤细胞生长，并且一致地，PADI 4的敲低减弱了p53介导的生长抑制活性，证明了PADI 4介导的瓜氨酸蛋白在p53信号传导途径中的重要性。[Cancer Res 2009;69（22）：8761-9]
Upon a wide range of cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes related to apoptosis, cell cycle arrest, and DNA repair. However, its involvement in posttranslational modifications of proteins has not yet been well characterized. Here, we report the novel role of p53 in the regulation of protein citrullination. p53 transactivated peptidylarginine deiminase type 4 (PADI4) through an intronic p53-binding site. The PADI4 gene encodes an enzyme catalyzing the citrullination of arginine residues in proteins, and ectopic expression of p53 or PADI4 induced protein citrullination. In addition, various proteins were citrullinated in response to DNA damage, but knockdown of PADI4 or p53 remarkably inhibited their citrullination, indicating the regulation of protein citrullination in a p53/PADI4-dependent manner. We found that PADI4 citrullinated the histone chaperone protein, nucleophosmin (NPM1), at the arginine 197 residue in vivo under physiologic conditions. Citrullination of NPM1 by PADI4 resulted in its translocation from the nucleoli to the nucleoplasm, whereas PADI4 did not alter the localization of mutant NPM1 (R197K). Furthermore, ectopic expression of PADI4 inhibited tumor cell growth, and concordantly, the knockdown of PADI4 attenuated p53-mediated growth-inhibitory activity, demonstrating the significance of PADI4-mediated protein citrullination in the p53 signaling pathway. [Cancer Res 2009;69(22):8761-9]