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首页> 外文期刊>Cell cycle >MdmX inhibits ARF mediated Mdm2 sumoylation.
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MdmX inhibits ARF mediated Mdm2 sumoylation.

机译：MdmX抑制ARF介导的Mdm2 sumoylation。

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摘要

Mdm2, by virtue of an intrinsic E3 ubiquitin ligase activity, is capable of autoubiquitination and the ubiquitination of the p53 tumor suppressor protein. Additionally, Hdm2 has been reported to undergo a p14ARF-dependent sumoylation with concurrent Hdm2 stabilization. In this present work, we report that MdmX can undergo ARF-mediated sumoylation similar to that reported for Mdm2. When coexpressed, MdmX overexpression results in a dose-dependent inhibition of Mdm2 sumoylation and a concurrent increase in Mdm2 ubiquitination. This switch from Mdm2 sumoylation to Mdm2 ubiquitination may explain the destablization of Mdm2 previously observed in cells overexpressing both ARF and MdmX. Given that MdmX can heterodimerize with Mdm2 and separately associate with ARF we employed a series of MdmX mutants to examine how MdmX blocks Mdm2 sumoylation. A MdmX miniprotein capable of binding to ARF, but not p53 or Mdm2 was able to competitively inhibit Mdm2 sumoylation and reverse ARF mediated activation of p53 transactivation. Taken together, these results demonstrate that MdmX can affect post-translational modification and stability of Mdm2 and p53 activity through interaction with ARF.
机译：Mdm2凭借固有的E3泛素连接酶活性，能够进行p53肿瘤抑制蛋白的自身泛素化和泛素化。此外，据报道Hdm2经历了p14ARF依赖的磺酰化反应，同时具有Hdm2稳定作用。在本工作中，我们报告说MdmX可以经历类似于Mdm2报道的ARF介导的磺酰化反应。当共表达时，MdmX过表达导致Mdm2 sumoylation的剂量依赖性抑制和Mdm2泛素化的同时增加。从Mdm2磺酰化到Mdm2泛素化的这种转变可能解释了先前在过表达ARF和MdmX的细胞中观察到的Mdm2的去稳定化。鉴于MdmX可以与Mdm2异源二聚体并分别与ARF缔合，我们采用了一系列MdmX突变体来研究MdmX如何阻止Mdm2 sumoylation。能够与ARF结合但不与p53或Mdm2结合的MdmX小蛋白能够竞争性地抑制Mdm2 sumoylation和逆转ARF介导的p53反式激活。两者合计，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。

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