The E3 Ligase RING1 Targets p53 for Degradation and Promotes Cancer Cell Proliferation and Survival
The E3 Ligase RING1 Targets p53 for Degradation and Promotes Cancer Cell Proliferation and Survival
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E3 连接酶 RING1 以 p53 为目标进行降解，并促进癌细胞增殖和存活。
DOI：
10.1158/0008-5472.can-17-1805
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发表时间：
2018-01-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Zhen
中科院分区：
文献类型：
--
作者：
Shen, Jiajia;Li, Pengyu;Wang, Zhen
环指蛋白RING 1作为转录抑制复合物1（PRC 1）的组成部分，参与癌症的表观遗传调控。然而，RING 1对癌症病因学或发展的贡献是未知的。在这项研究中，我们报告说，RING 1是一个关键的负调节人肝细胞癌和结直肠癌的p53稳态。RING 1作为E3泛素（Ub）连接酶直接与p53相互作用并使其泛素化，导致其蛋白酶体依赖性降解。RING 1的RING结构域是其E3 Ub连接酶活性所必需的。RING 1耗竭通过诱导细胞周期停滞、凋亡和衰老抑制p53野生型癌细胞的增殖和存活，对p53缺陷细胞仅有适度的影响。其生长抑制作用部分被p53沉默拯救，表明RING 1-p53复合物在人类癌症中的重要作用。在肝细胞癌的临床标本中，RING 1上调与不良临床结局明显相关。总的来说，我们的研究结果阐明了一种新的PRC 1独立功能的RING 1和提供一个机制的理由，其候选人作为一个新的预后标志物和/或治疗靶点在人类cancer.Significance：这些结果阐明了一种新的PRC 1独立功能的RING 1和提供一个机制的理由，其候选人作为一个新的预后标志物和/或治疗靶点在人类癌症。Cancer Res; 78（2）; 359-71.©2017 AACR.
As a component of the transcriptional repression complex 1 (PRC1), the ring finger protein RING1 participates in the epigenetic regulation in cancer. However, the contributions of RING1 to cancer etiology or development are unknown. In this study, we report that RING1 is a critical negative regulator of p53 homeostasis in human hepatocellular and colorectal carcinomas. RING1 acts as an E3 ubiquitin (Ub) ligase to directly interact with and ubiquitinate p53, resulting in its proteasome-dependent degradation. The RING domain of RING1 was required for its E3 Ub ligase activity. RING1 depletion inhibited the proliferation and survival of the p53 wild-type cancer cells by inducing cell-cycle arrest, apoptosis, and senescence, with only modest effects on p53-deficient cells. Its growth inhibitory effect was partially rescued by p53 silencing, suggesting an important role for the RING1-p53 complex in human cancer. In clinical specimens of hepatocellular carcinoma, RING1 upregulation was evident in association with poor clinical outcomes. Collectively, our results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer.Significance: These results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer. Cancer Res; 78(2); 359-71. ©2017 AACR.