Hdm2 通过将 p53 隔离在核内来破坏 HdmX 介导的 p53 核输出。

Hdm2 disrupts HdmX-mediated nuclear export of p53 by sequestering it in nucleus.

机构信息

MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China; Centre for Optical and Electromagnetic Research, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou, 510631, China.

出版信息

Exp Cell Res. 2024 Aug 15;441(2):114185. doi: 10.1016/j.yexcr.2024.114185. Epub 2024 Jul 26.

DOI:10.1016/j.yexcr.2024.114185

PMID:39069150

Abstract

Dysfunction of the tumor suppressor p53 occurs in most human cancers, Hdm2 and HdmX play critical roles in p53 inactivation and degradation. Under unstressed conditions, HdmX binds to p53 like Hdm2, but HdmX cannot directly induce p53 degradation. Moreover, HdmX has been reported to stimulate Hdm2-mediated ubiquitination and degradation of p53. Here we reported that HdmX promoted the nuclear export of p53 independent of Hdm2 in living cells using FRET technology. Whereas, Hdm2 impeded HdmX-mediated nuclear export of p53 by sequestering it in nucleus. Interestingly, the C-terminal RING domain mutant Hdm2 formed heterooligomers with p53 in nucleus, which was inhibited by HdmX. The heterooligomers were located near PML-NBs. This study indicate that the nuclear Hdm2-HdmX interaction aborts the HdmX-mediated nuclear export of p53.

摘要

抑癌基因 p53 的失活存在于大多数人类肿瘤中，Hdm2 和 HdmX 在 p53 的失活和降解中起着关键作用。在未受应激的条件下，HdmX 与 Hdm2 结合 p53，但 HdmX 不能直接诱导 p53 降解。此外，已有报道称 HdmX 可刺激 Hdm2 介导的 p53 的泛素化和降解。本研究利用 FRET 技术，在活细胞中报道了 HdmX 独立于 Hdm2 促进 p53 的核输出。然而，Hdm2 通过将其隔离在核内来阻止 HdmX 介导的 p53 的核输出。有趣的是，核内 RING 结构域突变体 Hdm2 与 p53 形成异源寡聚体，这一过程被 HdmX 抑制。这些异源寡聚体位于 PML-NBs 附近。本研究表明，核内 Hdm2-HdmX 相互作用可阻断 HdmX 介导的 p53 的核输出。