MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation
MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation
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DOI：
10.1038/sj.emboj.7600791
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发表时间：
2005-09-21
期刊：
影响因子：
11.4
通讯作者：
Chen, JD
中科院分区：
文献类型：
--
作者：
Wang, CG;Ivanov, A;Chen, JD
MDM 2是一种RING结构域泛素E3连接酶，是p53肿瘤抑制因子的主要调节因子。MDM 2与p53结合，使p53转录功能失活，抑制p53乙酰化，并促进p53降解。在这里，我们提出的证据表明，MDM 2与核辅阻遏物KAP 1相互作用。这种结合是由KAP 1的N-末端卷曲螺旋结构域和MDM 2的中心酸性结构域介导的。KAP 1通过与MDM 2相互作用刺激p53 -HDAC 1复合物的形成并抑制p53乙酰化。KAP 1的表达与MDM 2协同促进p53泛素化和降解。肿瘤抑制因子ARF与KAP 1竞争MDM 2结合;癌基因诱导ARF表达减少MDM 2与KAP 1的相互作用。通过RNAi消除内源性KAP 1表达刺激p53转录活性，使p53对DNA损伤的反应敏感，并增加细胞凋亡。因此，MDM 2与KAP 1的相互作用有助于p53功能调节。ARF可能部分通过抑制KAP 1 MDM 2结合来调节p53乙酰化和稳定性。
MDM2 is a RING domain ubiquitin E3 ligase and a major regulator of the p53 tumor suppressor. MDM2 binds to p53, inactivates p53 transcription function, inhibits p53 acetylation, and promotes p53 degradation. Here, we present evidence that MDM2 interacts with the nuclear corepressor KAP1. The binding is mediated by the N-terminal coiled-coil domain of KAP1 and the central acidic domain of MDM2. KAP1 stimulates formation of p53 - HDAC1 complex and inhibits p53 acetylation by interacting with MDM2. Expression of KAP1 cooperates with MDM2 to promote p53 ubiquitination and degradation. The tumor suppressor ARF competes with KAP1 in MDM2 binding; oncogene induction of ARF expression reduces MDM2 KAP1 interaction. Depletion of endogenous KAP1 expression by RNAi stimulates p53 transcriptional activity, sensitizes p53 response to DNA damage, and increases apoptosis. Therefore, MDM2 interaction with KAP1 contributes to p53 functional regulation. ARF may regulate p53 acetylation and stability in part by inhibiting KAP1 MDM2 binding.