Walter and Eliza Hall醫(yī)學(xué)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(gè)研究中心的科學(xué)家近日在Nature在線(xiàn)版上發(fā)表泛素化與癌癥的相關(guān)研究成果文章,。
MCL1是維持祖細(xì)胞和干細(xì)胞多能性的重要基因,，并且在泛素化的過(guò)程中MCL1對(duì)BCL2前體存活也具有重要的意義,。淋巴瘤細(xì)胞株的髓細(xì)胞白血病和多樣性骨髓瘤都具有異常的MCL1基因表達(dá)量,，過(guò)高的MCL1表達(dá)量會(huì)促進(jìn)癌癥細(xì)胞對(duì)化療產(chǎn)生抗藥性,，并且能促使癌癥復(fù)發(fā)。而關(guān)于MCL1過(guò)量表達(dá)的機(jī)制卻了解不多,。
在本研究中,，科學(xué)家們發(fā)現(xiàn)去泛素化酶USP9X具有穩(wěn)定MCL1表達(dá)，維持癌細(xì)胞穩(wěn)定的功效,。USP9X能結(jié)合在MCL1上,，并停止Lys48連接的多聚泛素化鏈反應(yīng)。在淋巴瘤和B細(xì)胞淋巴瘤中,，增加USP9X的表達(dá)量可促進(jìn)MCL1蛋白的表達(dá)量,。
USP9X為廣泛表達(dá)的一個(gè)基因，其編碼蛋白為泛素水解酶,。
此外,，研究發(fā)現(xiàn)USP9X過(guò)量表達(dá)的患者往往預(yù)后不良，敲除USP9X可增加MCL1的泛素化活性,，可有效改變MCL1的表達(dá),。
這些結(jié)果都表明，USP9X是癌癥患者預(yù)后的評(píng)價(jià)標(biāo)志,，也可能是一個(gè)新的癌癥治療靶位,。去泛素化可能是癌細(xì)胞維持穩(wěn)定的機(jī)制。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
