Regulation of Mdm2-directed degradation by the C terminus of p53
Regulation of Mdm2-directed degradation by the C terminus of p53
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DOI：
10.1128/mcb.18.10.5690
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发表时间：
1998-10-01
影响因子：
5.3
通讯作者：
Vousden, KH
中科院分区：
文献类型：
--
作者：
Kubbutat, MHG;Ludwig, RL;Vousden, KH
P53抑癌蛋白的稳定性通过与MDM2的相互作用来调节，MDM2是P53诱导基因的产物。MDM2靶向降解P53依赖于两种蛋白之间的相互作用，并通过蛋白酶体介导。我们在这里表明，除了N端的MDM2结合域外，P53的C端还参与了P53被MDM2降解的能力。相反，P53中心DNA结合域的改变改变了P53蛋白的构象，并不会消除该蛋白对MDM2介导的降解的敏感性。C末端寡聚域对MDM2靶向降解p53的重要性可能反映了全长p53蛋白的寡聚对与MDM2相互作用的重要性，如先前在体外显示的那样。有趣的是，P53的极端C-末端区域在寡聚化结构域之外，也被证明是有效降解所必需的，该区域的缺失在不破坏其与MDM2结合的能力的情况下稳定了蛋白质。在DNA损伤后，耐MDM2的p53突变体不再进一步稳定，支持MDM2作为细胞内p53稳定性的主要调节因子的作用。P53蛋白的极端C末端先前已被证明包含几个调控元件，这增加了该结构域对P53的变构调节或该区域与第三种蛋白之间的相互作用在决定P53对MDM2导向的降解的敏感性方面的可能性。
The stability of the p53 tumor suppressor protein is regulated by interaction with Mdm2, the product of a p53-inducible gene. Mdm2-targeted degradation of p53 depends on the interaction between the two proteins and is mediated hv the proteasome. We show here that in addition to the N-terminal Mdm2 binding domain, the C terminus of p53 participates in the ability of p53 to be degraded by Mdm2. In contrast, alterations in the central DNA binding domain of p53, which change the conformation of the p53 protein, do not abrogate the sensitivity of the protein to Mdm2-mediated degradation. The importance of the C-terminal oligomerization domain to Mdm2-targeted degradation of p53 is likely to reflect the importance of oligomerization of the full-length p53 protein for interaction with Mdm2, as previously shown in vitro. Interestingly, the extreme C-terminal region of p53, outside the oligomerization domain, was also shown to be necessary for efficient degradation, and deletion of this region stabilized the protein without abrogating its ability to bind to Mdm2. Mdm2-resistant p53 mutants were not further stabilized following DNA damage, supporting a role for Mdm2 as the principal regulator of p53 stability in cells. The extreme C terminus of the p53 protein has previously been shown to contain several regulatory elements, raising the possibility that either allosteric regulation of p53 by this domain or interaction between this region and a third protein plays a role in determining the sensitivity of p53 to Mdm2-directed degradation.