Late Cornified Envelope Group I, a novel target of p53, regulates PRMT5 activity.
Late Cornified Envelope Group I, a novel target of p53, regulates PRMT5 activity.
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DOI：
10.1016/j.neo.2014.07.008
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发表时间：
2014-08
期刊：
影响因子：
4.8
通讯作者：
Nakamura, Yusuke
中科院分区：
文献类型：
--
作者：
Deng, Zhenzhong;Matsuda, Koichi;Tanikawa, Chizu;Lin, Jiaying;Furukawa, Yoichi;Hamamoto, Ryuji;Nakamura, Yusuke
P53是人类致癌过程中最重要的抑癌基因之一。虽然P53下游靶点及其在癌细胞中的生物学功能已经得到了广泛的研究，但仍远未完全了解。在这里，我们证明了晚期角化包膜蛋白I(LCE1)基因位于LCE基因簇中，编码多种保守的角质层-角质层蛋白，是P53下游的新靶点。腺病毒载体系统外源P53的过表达显著增强了LCE1簇基因的表达。我们还观察到DNA损伤诱导LCE1的表达，这种损伤是由阿霉素或紫外线照射以野生型P53依赖的方式引起的。相应地，DNA损伤对LCE1的诱导作用被P53基因敲除后显著减弱。在预测的LCE1基因簇内的P53结合位点中，我们通过报告分析证实了其中一个位点是P53增强子序列。此外，我们还鉴定了LCE1与精氨酸甲基转移酶5(PRMT5)蛋白相互作用。PRMT5底物组蛋白H3精氨酸8的对称二甲基化水平显著高于LCE1，而LCE1F的过表达显著降低其甲基化水平。我们的数据表明，LCE1是一个新的P53下游靶点，可以被P53直接反式激活，并可能通过调节PRMT5的活性而具有肿瘤抑制功能。
p53 is one of the most important tumor suppressor genes involved in human carcinogenesis. Although downstream targets of p53 and their biologic functions in cancer cells have been extensively investigated, it is still far from the full understanding. Here, we demonstrate that Late Cornified Envelope Group I (LCE1) genes, which are located in the LCE gene clusters encoding multiple well-conserved stratum-corneum proteins, are novel downstream targets of p53. Exogenous p53 overexpression using an adenoviral vector system significantly enhanced the expression of LCE1 cluster genes. We also observed induction of LCE1 expressions by DNA damage, which was caused by treatment with adriamycin or UV irradiation in a wild-type p53-dependent manner. Concordantly, the induction of LCE1 by DNA damage was significantly attenuated by the knockdown of p53. Among predicted p53-binding sites within the LCE1 gene cluster, we confirmed one site to be a p53-enhancer sequence by reporter assays. Furthermore, we identified LCE1 to interact with protein arginine methyltransferase 5 (PRMT5). Knockdown of LCE1 by specific small interfering RNAs significantly increased the symmetric dimethylation of histone H3 arginine 8, a substrate of PRMT5, and overexpression of LCE1F remarkably decreased its methylation level. Our data suggest that LCE1 is a novel p53 downstream target that can be directly transactivated by p53 and is likely to have tumor suppressor functions through modulation of the PRMT5 activity.
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DOI：
10.1042/bj20120768
发表时间：
2012-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Gu Z;Gao S;Zhang F;Wang Z;Ma W;Davis RE;Wang Z
通讯作者：
Wang Z
影响因子：
37.3
作者：
Hayami S;Yoshimatsu M;Veerakumarasivam A;Unoki M;Iwai Y;Tsunoda T;Field HI;Kelly JD;Neal DE;Yamaue H;Ponder BA;Nakamura Y;Hamamoto R
通讯作者：
Hamamoto R
影响因子：
3.7
作者：
Nicholas C;Yang J;Peters SB;Bill MA;Baiocchi RA;Yan F;Sïf S;Tae S;Gaudio E;Wu X;Grever MR;Young GS;Lesinski GB
通讯作者：
Lesinski GB
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
6.5
作者：
Mischke, D;Korge, BP;Ziegler, A
通讯作者：
Ziegler, A