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    Walter and Eliza Hall醫學研究所,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個研究中心的科學家近日在Nature在線版上發表泛素化與癌癥的相關研究成果文章。







    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.

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