HDMX 通过 ATM 激酶的激活来折叠新生的 p53 mRNA。

HDMX folds the nascent p53 mRNA following activation by the ATM kinase.

机构信息

Cibles Thérapeutiques, Equipe Labellisée Ligue Contre le Cancer, INSERM Unité 940, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 27 rue Juliette Dodu, 75010 Paris, France.

出版信息

Mol Cell. 2014 May 8;54(3):500-11. doi: 10.1016/j.molcel.2014.02.035.

DOI:10.1016/j.molcel.2014.02.035

PMID:24813712

Abstract

Regulated protein synthesis via changes in mRNA structures forms an important part of how prokaryotic cells adapt protein expression in response to changes in the environment. Little is known regarding how this concept has adapted to regulate mRNA translation via signaling pathways in mammalian cells. Here, we show that following phosphorylation by the ataxia telangiectasia mutated (ATM) kinase at serine 403, the C-terminal RING domain of HDMX binds the nascent p53 mRNA to promote a conformation that supports the p53 mRNA-HDM2 interaction and the induction of p53 synthesis. HDMX and its homolog HDM2 bind the same p53 internal ribosome entry sequences (IRES) structure but with different specificity and function. The results show how HDMX and HDM2 act as nonredundant IRES trans-acting factors (ITAFs) to bring a positive synergistic effect on p53 expression during genotoxic stress by first altering the structure of the newly synthesized p53 mRNA followed by stimulation of translation.

摘要

通过改变 mRNA 结构来调节蛋白质合成，这是原核细胞响应环境变化调节蛋白质表达的重要方式。目前对于这一概念如何通过信号通路来调节哺乳动物细胞中的 mRNA 翻译还知之甚少。在这里，我们发现，在 ATM 激酶磷酸化丝氨酸 403 之后，HDMX 的 C 端 RING 结构域与新生的 p53 mRNA 结合，促进支持 p53 mRNA-HDM2 相互作用和 p53 合成诱导的构象。HDMX 和其同源物 HDM2 结合相同的 p53 内部核糖体进入序列 (IRES) 结构，但具有不同的特异性和功能。结果表明，HDMX 和 HDM2 如何作为非冗余的 IRES 反式作用因子（ITAF），通过首先改变新合成的 p53 mRNA 的结构，然后刺激翻译，在遗传毒性应激期间对 p53 表达产生积极的协同效应。