Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding
Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding
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DOI：
10.1074/jbc.m710030200
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发表时间：
2008-05-16
影响因子：
4.8
通讯作者：
Yuan, Zhi-Min
中科院分区：
文献类型：
--
作者：
Lopez-Pajares, Vanessa;Kim, Mihee M.;Yuan, Zhi-Min
几乎所有癌症中关键的肿瘤抑制因子 p53 都会发生突变或功能失活。我们之前已经证明，MDM2-MDMX 复合物作为一个整体单元，以 p53 为目标进行降解。在这里，我们将小蛋白 14-3-3 确定为 MDMX 的结合伴侣，它以磷酸化依赖性方式结合在 C 末端 (Ser367)。重要的是，我们证明丝氨酸/苏氨酸激酶 Akt 介导 MDMX Ser367 的磷酸化。这种磷酸化导致 MDMX 的稳定以及随之而来的 MDM2 的稳定。先前的研究表明 Akt 磷酸化并稳定 MDM2。我们的数据表明，Akt 对 MDMX 的稳定可能是 Akt 上调 MDM2 蛋白水平并对肿瘤细胞中的 p53 发挥致癌作用的另一种机制。
The critical tumor suppressor p53 is mutated or functionally inactivated in nearly all cancers. We have shown previously that the MDM2-MDMX complex functions as an integral unit in targeting p53 for degradation. Here we identify the small protein 14-3-3 as a binding partner of MDMX, which binds at the C terminus (Ser367) in a phosphorylation-dependent manner. Importantly, we demonstrate that the serine/threonine kinase Akt mediates phosphorylation of MDMX at Ser367. This phosphorylation leads to stabilization of MDMX and consequent stabilization of MDM2. Previous studies have shown that Akt phosphorylates and stabilizes MDM2. Our data suggest that stabilization of MDMX by Akt may be an alternative mechanism by which Akt up-regulates MDM2 protein levels and exerts its oncogenic effects on p53 in tumor cells.