The contribution of the RING finger domain of MDM2 to cell cycle progression
The contribution of the RING finger domain of MDM2 to cell cycle progression
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DOI：
10.1038/sj.onc.1203737
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发表时间：
2000-08-10
期刊：
影响因子：
8
通讯作者：
Wasylyk, B
中科院分区：
文献类型：
--
作者：
Argentini, M;Barboule, N;Wasylyk, B
MDM2 癌蛋白与 p53 结合并消除 p53 介导的 G1 停滞和细胞凋亡。我们表明，MDM2 过表达通过克服内源性野生型 p53 在 G1/S 检查点的负面影响，加速 RPMI2650 细胞的细胞周期进程。与 p53 和转录抑制的相互作用是必要的，但还不够。MDM2 对细胞周期的积极作用也需要 MDM2 的环指结构域。令人惊讶的是，环指锌结合位点的几个点突变体完全能够刺激细胞周期，即使它们消除了 MDM2 定向的 p53 降解和 MDM2 E3 连接酶活性。相反，隐性核仁定位序列（KR基序）及其周围的改变会抑制MDM2介导的细胞周期进程以及p53降解和MDM2 E3连接酶活性。我们发现所有RING突变体都会减少对p53依赖性报告基因和内源性p21（CIP1/WAF1/SDI1）的抑制。这些结果表明MDM2的RING指在细胞周期的调节中发挥作用，该作用独立于p53降解和内源性p21(CIP1/WAF1/SDI1)调节。
The MDM2 oncoprotein binds to p53 and abrogates p53-mediated G1 arrest and apoptosis, We show that MDM2 over-expression accelerates cell cycle progression of RPMI2650 cells by overcoming the negative effect of endogenous wild type p53 at the G1/S checkpoint. The interaction with p53 and transcription inhibition are necessary but not sufficient, The RING finger domain of MDM2 is also required for the positive effect of MDM2 on the cell cycle, Surprisingly, several point mutants in the zinc binding sites of the RING finger are fully competent for cell cycle stimulation even though they abolish MDM2-directed degradation of p53 and MDM2 E3-ligase activity. In contrast, alterations in and around the cryptic nucleolar localization sequence (KR motif) inhibit MDM2-mediated cell cycle progression as well as p53 degradation and MDM2 E3 ligase activity, We found that all the RING mutants decrease inhibition of both p53 dependent reporters and endogenous p21(CIP1/WAF1/SDI1). These results indicate that the RING finger of MDM2 has a role in the regulation of the cell cycle that is independent of p53 degradation and endogenous p21(CIP1/WAF1/SDI1) regulation.