Heat shock protein gp96 decreases p53 stability by regulating Mdm2 E3 ligase activity in liver cancer
Heat shock protein gp96 decreases p53 stability by regulating Mdm2 E3 ligase activity in liver cancer
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肝癌中热休克蛋白 gp96 通过调节 Mdm2 E3 连接酶活性降低 p53 稳定性
DOI：
10.1016/j.canlet.2015.01.034
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发表时间：
2015-04-10
期刊：
影响因子：
9.7
通讯作者：
Meng, Songdong
中科院分区：
文献类型：
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作者：
Wu, Bo;Chu, Xiaoyu;Meng, Songdong
肝癌表现出的对凋亡的抵抗在肝癌的发生、肿瘤进展以及对化疗或放射治疗的抵抗中起着关键作用。在本研究中，我们揭示了热休克蛋白gp96在调节肝肿瘤细胞生长和凋亡中的潜在作用和机制。通过对gp96基因敲除的肝癌细胞中的凋亡相关蛋白的分析，确定p53蛋白为gp96客户蛋白。过表达和基因敲除研究都表明gp96降低了P53蛋白水平，并且gp96以P53依赖的方式调节细胞的凋亡。我们进一步提供的证据表明，gp96与p53和MDM2相互作用，促进MDM2介导的p53泛素化和降解。此外，靶向gp96的siRNA可诱导细胞凋亡，抑制体内肝肿瘤的生长。综上所述，我们阐明了gp96通过增加MDM2 E3连接酶活性促进P53降解的潜在机制，并为靶向gp96介导的肝细胞癌的抗凋亡特性提供了新的治疗策略。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
The resistance to apoptosis displayed by liver cancer plays a key role in hepatocarcinogenesis, tumor progression, and resistance to chemo- or radio-therapy. In this study, we uncovered the potential role and mechanism of heat shock protein gp96 in regulating liver tumor cell growth and apoptosis. P53 protein was identified as a gp96 client protein by profiling apoptosis-related proteins in gp96-knockdown liver cancer cells. Overexpression and knockdown studies both demonstrated that gp96 decreases p53 protein levels, and gp96 regulated cell apoptosis in a p53-dependent manner. We further provide evidence that gp96 interacts with both p53 and Mdm2 to enhance Mdm2-mediated p53 ubiquitination and degradation. Moreover, targeting gp96 with siRNA induced cell apoptosis and led to the suppression of liver tumor growth in vivo. In conclusion, we elucidated an underlying mechanism by which gp96 promotes p53 degradation via increasing Mdm2 E3 ligase activity and provided a new therapeutic strategy to target the gp96-mediated anti-apoptotic characteristic of hepatocellular carcinoma. (C) 2015 Elsevier Ireland Ltd. All rights reserved.