...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular and Cellular Biology >Hypophosphorylation of Mdm2 Augments p53 Stability
【24h】

Hypophosphorylation of Mdm2 Augments p53 Stability

机译：Mdm2的次磷酸化增强p53稳定性

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The Mdm2 protein mediates ubiquitylation and degradation of p53 and is a key regulator of this tumor suppressor. More recently, it has been shown that Mdm2 is highly phosphorylated within its central acidic domain. In order to address the issue of how these modifications might regulate Mdm2 function, putative phosphorylation sites within this domain were substituted, individually or in pairs, with alanine residues. Mutants with serine-to-alanine substitutions between residues 244 and 260 abolished or at least reduced the capacity of Mdm2 to promote p53 degradation. In each case, loss of degradation function was independent of the ability to bind to p53 or p14ARF. Moreover, each of the Mdm2 mutants completely retained the capacity to act as a ubiquitin ligase in vivo. Thus, ubiquitylation and degradation can be uncoupled. Two-dimensional phosphopeptide mapping coupled with the use of phospho-specific antibodies revealed that Mdm2 is phosphorylated physiologically at several sites within this region, consistent with the idea that phosphorylation is important for Mdm2 activity. Strikingly, treatment of cells with ionizing radiation resulted in a significant decrease in the phosphorylation of residues that are important for p53 turnover. This hypophosphorylation preceded p53 accumulation. These findings indicate that Mdm2 contributes an additional function toward the degradation of p53 that is distinct from its ubiquitin ligase activity and is regulated by phosphorylation. Our model suggests that hypophosphorylation of Mdm2 in response to ionizing irradiation inactivates this novel function, thereby contributing to p53 stabilization.
机译：Mdm2蛋白介导p53的泛素化和降解，是该肿瘤抑制因子的关键调节因子。最近，已经显示出Mdm2在其中心酸性结构域内被高度磷酸化。为了解决这些修饰如何调节Mdm2功能的问题，该域中的假定磷酸化位点被单独或成对地替换为丙氨酸残基。在残基244和260之间具有丝氨酸至丙氨酸取代的突变体消除或至少降低了Mdm2促进p53降解的能力。在每种情况下，降解功能的丧失均与结合p53或p14ARF的能力无关。此外，每个Mdm2突变体完全保留了在体内充当泛素连接酶的能力。因此，泛素化和降解可以解偶联。二维磷酸肽作图结合磷酸特异性抗体的使用表明，Mdm2在该区域内的多个位点生理上被磷酸化，这与磷酸化对于Mdm2活性很重要的想法一致。令人惊讶的是，用电离辐射处理细胞导致对p53转换至关重要的残基的磷酸化显着降低。这种低磷酸化发生在p53积累之前。这些发现表明，Mdm2对p53的降解具有额外的功能，这与其泛素连接酶活性不同，并受磷酸化作用调节。我们的模型表明，Mdm2的低磷酸化响应电离辐射会失活这一新功能，从而有助于p53的稳定。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号