EDD Inhibits ATM-mediated Phosphorylation of p53
EDD Inhibits ATM-mediated Phosphorylation of p53
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DOI：
10.1074/jbc.m110.182527
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发表时间：
2011-04-29
影响因子：
4.8
通讯作者：
Lin, Weei-Chin
中科院分区：
文献类型：
--
作者：
Ling, Shiyun;Lin, Weei-Chin
EDD（E3 identified by differential display）基因首先在T-47 D乳腺癌细胞中被鉴定为孕激素诱导的基因，编码具有HECT结构域的E3泛素连接酶。据报道，EDD通过磷酸化katanin p60的泛素化参与G（2）/M进展。先前的研究也表明EDD可以作为转录辅因子独立于其E3连接酶活性。在这项研究中，我们发现了一个新的作用，EDD在细胞周期的进程中，在E3连接酶的独立方式。我们证明，EDD可以物理相互作用与p53，这种相互作用阻断p53的磷酸化共济失调毛细血管扩张突变（ATM）。EDD的沉默诱导p53在Ser（15）处的磷酸化，并激活成纤维细胞和一些转化细胞中的p53靶基因，而不激活DNA损伤反应。EDD耗竭诱导的G（1）/S阻滞依赖于p53。另一方面，EDD的过表达抑制p53-Ser（15）磷酸化并抑制DNA损伤过程中p53靶基因的诱导，并且这种作用不需要其E3连接酶活性。因此，通过与p53结合，EDD积极抑制ATM对p53的磷酸化，并在确保G（1）/S进展顺利中发挥作用。
The EDD (E3 identified by differential display) gene, first identified as a progestin-induced gene in T-47D breast cancer cells, encodes an E3 ubiquitin ligase with a HECT domain. It was reported that EDD is involved in the G(2)/M progression through ubiquitination of phospho-katanin p60. Previous study has also shown that EDD can act as a transcription cofactor independently of its E3 ligase activity. In this study, we uncover a new role for EDD during cell cycle progression in an E3 ligase-independent manner. We demonstrate that EDD can physically interact with p53 and that this interaction blocks the phosphorylation of p53 by ataxia telangiectasia mutated (ATM). Silencing of EDD induces phosphorylation of p53 at Ser(15) and activates p53 target genes in fibroblasts and some transformed cells without activation of DNA damage response. The G(1)/S arrest induced by EDD depletion depends on p53. On the other hand, overexpression of EDD inhibits p53-Ser(15) phosphorylation and suppresses the induction of p53 target genes during DNA damage, and this effect does not require its E3 ligase activity. Thus, through binding to p53, EDD actively inhibits p53 phosphorylation by ATM and plays a role in ensuring smooth G(1)/S progression.