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核仁定位的 RelA(p65) 受 COMMD1 依赖性泛素化调节。

Nucleolar targeting of RelA(p65) is regulated by COMMD1-dependent ubiquitination.

机构信息

Colon Cancer Genetics Group, University of Edinburgh Cancer Research Centre and MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom.

出版信息

Cancer Res. 2010 Jan 1;70(1):139-49. doi: 10.1158/0008-5472.CAN-09-1397.

Abstract

Stimulation of the NF-kappaB pathway can have proapoptotic or antiapoptotic consequences, and one mechanism that determines the outcome is the nuclear distribution of RelA. Certain stress stimuli induce nucleolar accumulation of RelA thereby mediating apoptosis, whereas others induce nucleoplasmic accumulation and inhibition of apoptosis. Here we investigated the mechanisms that regulate the nuclear distribution of RelA, specifically, the role of the ubiquitin/proteasome system. We found that stress-induced nucleolar translocation of RelA is preceded by ubiquitination of the protein. We also found that chemical proteasome inhibitors induce the ubiquitination and nucleolar translocation of RelA and that this is required for the apoptotic response to these agents. We show that the RelA nucleolar localization signal (amino acids 27-30) is a critical domain for ubiquitination of the protein but that the lysine residue within this motif is not a direct target. We show that RelA binds COMMD1, the rate-limiting component of the RelA ubiquitin ligase complex, in response to stress. Furthermore, we show that overexpression of COMMD1 promotes stress-mediated nucleolar targeting of RelA, whereas knockdown of COMMD1 blocks this effect, causing RelA to remain in the nucleoplasm. These data identify a new role for COMMD1 in regulating the nuclear/nucleolar distribution of RelA and suggest that ubiquitination acts as a signal for transport of RelA to the nucleolus. These findings have relevance to the design of chemopreventative/anticancer agents that act by targeting RelA to the nucleolar compartment.

摘要

NF-κB 通路的激活可产生促凋亡或抗凋亡的后果,而决定这一结果的机制之一是 RelA 的核分布。某些应激刺激诱导 RelA 核仁聚集,从而介导细胞凋亡,而其他刺激则诱导 RelA 核质聚集并抑制细胞凋亡。在这里,我们研究了调节 RelA 核分布的机制,特别是泛素/蛋白酶体系统的作用。我们发现应激诱导的 RelA 核仁易位是蛋白泛素化的前奏。我们还发现化学蛋白酶体抑制剂诱导 RelA 的泛素化和核仁易位,这是这些药物诱导凋亡反应所必需的。我们表明,RelA 的核仁定位信号(氨基酸 27-30)是该蛋白泛素化的关键结构域,但该基序内的赖氨酸残基不是直接靶标。我们表明,RelA 在应激反应中与 COMMD1 结合,COMMD1 是 RelA 泛素连接酶复合物的限速组成部分。此外,我们表明,COMMD1 的过表达促进了应激介导的 RelA 核仁靶向,而 COMMD1 的敲低则阻止了这一效应,导致 RelA 留在核质中。这些数据确定了 COMMD1 在调节 RelA 的核/核仁分布中的新作用,并表明泛素化作为 RelA 向核仁转运的信号。这些发现与设计通过将 RelA 靶向核仁区室来发挥作用的化学预防/抗癌药物有关。

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