HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway
HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway
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HUWE1 与 BRCA1 相互作用并促进其在泛素-蛋白酶体途径中的降解
DOI：
10.1016/j.bbrc.2013.12.053
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发表时间：
2014-02-14
影响因子：
3.1
通讯作者：
Shao, Genze
中科院分区：
文献类型：
--
作者：
Wang, Xiaozhen;Lu, Guang;Shao, Genze
细胞内BRCA1蛋白水平是其肿瘤抑制活性所必需的，并受到包括泛素-蛋白酶体系统在内的多种机制的严格调控。E3连接酶参与促进BRCA1的泛素化和降解。在此，我们发现HUWE1/Mule/ARF-BP1是一种新的BRCA1相互作用蛋白，参与BRCA1蛋白水平的调控。HUWE1通过其N-末端的降解结构域与BRCA1结合。通过siRNA介导的干扰耗尽HUWE1显著增加BRCA1的蛋白水平并延长BRCA1的半衰期。此外，HUWE1的外源表达通过泛素-蛋白酶体途径促进BRCA1的降解，这可能解释了在MCF10F、MCF7和MDA-MB-231乳腺癌细胞中HUWE1和BRCA1水平之间的负相关关系。与HUWE1在调节BRCA1介导的细胞对DNA损伤的反应中的功能一致，通过siRNA耗尽HUWE1可以增强对电离辐射和丝裂霉素的抵抗力。这些数据表明，HUWE1是BRCA1的关键负调控因子，并提示了乳腺癌发病的新的分子机制。(C)2014年，爱思唯尔公司出版。
The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn-proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1 binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half-life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin-proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1 -mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis. (C) 2014 published by Elsevier Inc.