p53mRNA-Mdm2 相互作用控制 Mdm2 的核转运，并且是 DNA 损伤后 p53 激活所必需的。

The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage.

机构信息

Cibles Therapeutiques, INSERM Unité, Institut de Génétique Moléculaire, Université Paris, IUH Hôpital St. Louis, Paris, France.

出版信息

Cancer Cell. 2012 Jan 17;21(1):25-35. doi: 10.1016/j.ccr.2011.11.016.

DOI:10.1016/j.ccr.2011.11.016

PMID:22264786

Abstract

The ATM kinase and p53 are key tumor suppressor factors that control the genotoxic stress response pathway. The ATM substrate Mdm2 controls p53 activity by either targeting p53 for degradation or promoting its synthesis by binding the p53 mRNA. The physiological role and regulation of Mdm2's dual function toward p53 is not known. Here we show that ATM-dependent phosphorylation of Mdm2 at Ser395 is required for the p53 mRNA-Mdm2 interaction. This event also promotes SUMO-conjugation of Mdm2 and its nucleoli accumulation. Interfering with the p53 mRNA-Mdm2 interaction prevents p53 stabilization and activation following DNA damage. These results demonstrate how ATM activity switches Mdm2 from a negative to a positive regulator of p53 via the p53 mRNA.

摘要

ATM 激酶和 p53 是控制遗传毒性应激反应途径的关键肿瘤抑制因子。ATM 底物 Mdm2 通过靶向 p53 降解或通过结合 p53 mRNA 促进其合成来控制 p53 活性。Mdm2 对 p53 的双重功能的生理作用和调节尚不清楚。在这里，我们表明 ATM 依赖性磷酸化 Mdm2 的丝氨酸 395 是 p53 mRNA-Mdm2 相互作用所必需的。这一事件还促进了 Mdm2 的 SUMO 缀合及其核仁积累。干扰 p53 mRNA-Mdm2 相互作用可防止 DNA 损伤后 p53 的稳定和激活。这些结果表明，ATM 活性如何通过 p53 mRNA 将 Mdm2 从 p53 的负调控因子转换为正调控因子。