Nature：去泛素化有助癌细胞维持稳定
Walter and Eliza Hall医学研究所，Genentech公司致癌基因研究中心，病理研究中心，生物信息研究中心等多个研究中心的科学家近日在Nature在线版上发表泛素化与癌症的相关研究成果文章。
MCL1是维持祖细胞和干细胞多能性的重要基因，并且在泛素化的过程中MCL1对BCL2前体存活也具有重要的意义。淋巴瘤细胞株的髓细胞白血病和多样性骨髓瘤都具有异常的MCL1基因表达量，过高的MCL1表达量会促进癌症细胞对化疗产生抗药性，并且能促使癌症复发。而关于MCL1过量表达的机制却了解不多。
在本研究中，科学家们发现去泛素化酶USP9X具有稳定MCL1表达，维持癌细胞稳定的功效。USP9X能结合在MCL1上，并停止Lys48连接的多聚泛素化链反应。在淋巴瘤和B细胞淋巴瘤中，增加USP9X的表达量可促进MCL1蛋白的表达量。
USP9X为广泛表达的一个基因，其编码蛋白为泛素水解酶。
此外，研究发现USP9X过量表达的患者往往预后不良，敲除USP9X可增加MCL1的泛素化活性，可有效改变MCL1的表达。
这些结果都表明，USP9X是癌症患者预后的评价标志，也可能是一个新的癌症治疗靶位。去泛素化可能是癌细胞维持稳定的机制。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature advance online publication 20 December 2009 | doi:10.1038/nature08646
Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival
Martin Schwickart1,9, XiaoDong Huang1,9, Jennie R. Lill2, Jinfeng Liu3, Ronald Ferrando4, Dorothy M. French4, Heather Maecker5, Karen O’Rourke1, Fernando Bazan6, Jeffrey Eastham-Anderson4, Peng Yue3, David Dornan7, David C. S. Huang8 & Vishva M. Dixit1
1 Department of Physiological Chemistry,
2 Department of Protein Chemistry,
3 Department of Bioinformatics,
4 Department of Pathology,
5 Department of Translational Oncology,
6 Department of Protein Engineering,
7 Department of Research Oncology Diagnostics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
8 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
9 These authors contributed equally to this work.
10 Correspondence to: Vishva M. Dixit1 Correspondence and requests for materials should be addressed to V.M.D.
MCL1 is essential for the survival of stem and progenitor cells of multiple lineages1, 2, and is unique among pro-survival BCL2 family members in that it is rapidly turned over through the action of ubiquitin ligases3, 4, 5, 6. B- and mantle-cell lymphomas, chronic myeloid leukaemia, and multiple myeloma7, 8, 9, however, express abnormally high levels of MCL1, contributing to chemoresistance and disease relapse. The mechanism of MCL1 overexpression in cancer is not well understood. Here we show that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival. USP9X binds MCL1 and removes the Lys?48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increases MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. These results identify USP9X as a prognostic and therapeutic target, and they show that deubiquitinases may stabilize labile oncoproteins in human malignancies.