MdmX Inhibits ARF Mediated Mdm2 Sumoylation
MdmX Inhibits ARF Mediated Mdm2 Sumoylation
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DOI：
10.4161/cc.4.4.1597
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发表时间：
2005-01
期刊：
影响因子：
4.3
通讯作者：
Mithua Ghosh;Karen Weghorst;S. Berberich
中科院分区：
文献类型：
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作者：
Mithua Ghosh;Karen Weghorst;S. Berberich
Mdm2 凭借内在的 E3 泛素连接酶活性，能够进行自身泛素化和 p53 肿瘤抑制蛋白的泛素化。此外，据报道，Hdm2 会经历 p14ARF 依赖性苏酰化，同时稳定 Hdm2。在目前的工作中，我们报道 MdmX 可以经历 ARF 介导的 sumoylation，类似于 Mdm2 报道的那样。当共表达时，MdmX 过度表达会导致 Mdm2 sumoylation 的剂量依赖性抑制以及 Mdm2 泛素化的同时增加。这种从 Mdm2 苏酰化到 Mdm2 泛素化的转变可能解释了之前在过表达 ARF 和 MdmX 的细胞中观察到的 Mdm2 不稳定现象。鉴于 MdmX 可以与 Mdm2 异二聚化并分别与 ARF 关联，我们采用了一系列 MdmX 突变体来检查 MdmX 如何阻断 Mdm2 sumoylation。能够结合ARF而非p53或Mdm2的MdmX微型蛋白能够竞争性抑制Mdm2sumoylation并逆转ARF介导的p53反式激活。总而言之，这些结果表明 MdmX 可以通过与 ARF 相互作用影响 Mdm2 和 p53 活性的翻译后修饰和稳定性。
Mdm2, by virtue of an intrinsic E3 ubiquitin ligase activity, is capable ofautoubiquitination and the ubiquitination of the p53 tumor suppressor protein.Additionally, Hdm2 has been reported to undergo a p14ARF-dependentsumoylationwith concurrent Hdm2 stabilization. In this present work, we reportthat MdmX can undergo ARF-mediated sumoylation similar to that reported forMdm2. When coexpressed, MdmX overexpression results in a dose-dependentinhibition of Mdm2 sumoylation and a concurrent increase in Mdm2ubiquitination. This switch from Mdm2 sumoylation to Mdm2 ubiquitination mayexplain the destablization of Mdm2 previously observed in cells overexpressingboth ARF and MdmX. Given that MdmX can heterodimerize with Mdm2 andseparately associate with ARF we employed a series of MdmX mutants toexamine how MdmX blocks Mdm2 sumoylation. A MdmX miniprotein capable ofbinding to ARF, but not p53 or Mdm2 was able to competitively inhibit Mdm2sumoylation and reverse ARF mediated activation of p53 transactivation. Takentogether, these results demonstrate that MdmX can affect post-translationalmodification and stability of Mdm2 and p53 activity through interaction with ARF.