BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
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BRCA1相关蛋白-1是一种需要去泛素化活性和核定位的肿瘤抑制剂。
DOI：
10.1158/0008-5472.can-08-0365
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Wilkinson KD
中科院分区：
文献类型：
--
作者：
Ventii KH;Devi NS;Friedrich KL;Chernova TA;Tighiouart M;Van Meir EG;Wilkinson KD
BAP1(BRCA1相关蛋白-1)是一种细胞功能未知的去泛素酶，在乳腺癌和肺癌中发生突变。在本研究中，我们通过研究BAP1对裸鼠肺癌细胞的致瘤性，首次证明了BAP1具有体内抑瘤活性。我们证明，BAP1满足真正的肿瘤抑制因子的另一个标准，因为BAP1的癌症相关突变导致蛋白质缺乏去泛素活性。我们首次证明了两个预测的核靶向基序中的一个是BAP1核定位所必需的，并且在肺癌细胞系中发现的截断突变导致BAP1无法定位到核。此外，我们证明去泛素化活性和核定位都是BAP1介导的裸鼠肿瘤抑制所必需的。我们发现BAP1通过影响细胞周期、加快G1/S检查点的进程、通过同时具有凋亡和坏死特征的过程来诱导细胞死亡，从而发挥其抑瘤作用。令人惊讶的是，BAP1介导的生长抑制不依赖于野生型BRCA1。由于去泛素酶是泛素蛋白酶体系统的组成部分，这一途径已成为抗癌药物的重要靶点。泛素化酶BAP1是一种肿瘤抑制因子，它的发现有助于进一步了解泛素蛋白酶体系统在肿瘤发生中的作用，并有助于发现肿瘤治疗的新靶点。
BAP1 (BRCA1-associated protein-1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have demonstrated for the first time that BAP1 has tumor suppressor activity in vivo by showing that BAP1 can suppress tumorigenicity of lung cancer cells in athymic nude mice. We show that BAP1 fulfills another criterion of a genuine tumor suppressor because cancer-associated mutations in BAP1 result in a protein deficient in deubiquitinating activity. We show for the first time that one of the two predicted nuclear targeting motifs is required for nuclear localization of BAP1 and that a truncation mutant found in a lung cancer cell line results in BAP1 that fails to localize to the nucleus. Furthermore, we demonstrate that deubiquitinating activity and nuclear localization are both required for BAP1-mediated tumor suppression in nude mice. We show that BAP1 exerts its tumor suppressor functions by affecting the cell cycle; speeding the progression through the G1/S checkpoint and inducing cell death via a process that has characteristics of both apoptosis and necrosis. Surprisingly, BAP1-mediated growth suppression is independent of wild-type BRCA1. Since deubiquitinating enzymes are components of the ubiquitin proteasome system, this pathway has emerged as an important target for anti-cancer drugs. The identification of the deubiquitinating enzyme BAP1 as a tumor suppressor may lead to further understanding of how the ubiquitin proteasome system contributes to cancer and aid in the identification of new targets for cancer therapy.