Ventii Karen H, Devi Narra S, Friedrich Kenneth L, Chernova Tatiana A, Tighiouart Mourad, Van Meir Erwin G, Wilkinson Keith D
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cancer Res. 2008 Sep 1;68(17):6953-62. doi: 10.1158/0008-5472.CAN-08-0365.
BRCA1-associated protein-1 (BAP1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have shown 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 BAP1 mutants are 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 show 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 G(1)-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. Because deubiquitinating enzymes are components of the ubiquitin proteasome system, this pathway has emerged as an important target for anticancer 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.
乳腺癌1号关联蛋白1（BAP1）是一种细胞功能未知的去泛素化酶，在乳腺癌和肺癌中发生突变。在本研究中，我们首次证明BAP1在体内具有肿瘤抑制活性，通过表明BAP1可以抑制无胸腺裸鼠中肺癌细胞的致瘤性。我们表明BAP1符合真正肿瘤抑制因子的另一个标准，因为与癌症相关的BAP1突变体在去泛素化活性方面存在缺陷。我们首次表明，两个预测的核定位基序之一是BAP1核定位所必需的，并且在肺癌细胞系中发现的一个截短突变体导致BAP1无法定位于细胞核。此外，我们表明去泛素化活性和核定位对于裸鼠中BAP1介导的肿瘤抑制都是必需的。我们表明BAP1通过影响细胞周期、加速通过G(1)-S检查点的进程以及通过具有凋亡和坏死特征的过程诱导细胞死亡来发挥其肿瘤抑制功能。令人惊讶的是，BAP1介导的生长抑制独立于野生型BRCA1。由于去泛素化酶是泛素蛋白酶体系统的组成部分，该途径已成为抗癌药物的重要靶点。去泛素化酶BAP1作为肿瘤抑制因子的鉴定可能会进一步加深对泛素蛋白酶体系统如何促进癌症的理解，并有助于确定癌症治疗的新靶点。
