Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3
Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3
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DOI：
10.1038/sj.emboj.7600656
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发表时间：
2005-05-04
期刊：
影响因子：
11.4
通讯作者：
Kato, J
中科院分区：
文献类型：
--
作者：
Yoneda-Kato, N;Tomoda, K;Kato, J
髓系白血病因子1（Myeloid leukemia factor 1，MLF 1）是由t（3;5）（q25.1;q34）染色体易位产生的白血病融合蛋白NPM-MLF 1。尽管MLF 1在包括造血干细胞在内的多种组织中正常表达，并且MLF 1的过表达与人类癌症的恶性转化相关，但关于MLF 1如何参与细胞生长的调节知之甚少。在这里，我们表明，MLF 1是一个负调节细胞周期进程的肿瘤抑制基因p53的上游功能。MLF 1诱导小鼠胚胎成纤维细胞中p53依赖性细胞周期停滞。这种作用需要一种新的结合伴侣，COP 9信号体的亚基3（CSN 3）。CSN 3蛋白水平的减少与小干扰RNA废除MLF 1诱导的G1期阻滞和基因毒性应激损伤p53的激活。此外，异位MLF 1表达和CSN 3敲低会反向影响内源性COP 1水平，COP 1是一种p53的泛素连接酶。COP 1的外源表达克服了MLF 1诱导的生长停滞。这些结果表明，MLF 1是p53的关键调节因子，并表明其通过新的CSN 3-COP 1途径参与白血病发生。
Myeloid leukemia factor 1 (MLF1) was first identified as the leukemic fusion protein NPM-MLF1 generated by the t(3;5)(q25.1;q34) chromosomal translocation. Although MLF1 expresses normally in a variety of tissues including hematopoietic stem cells and the overexpression of MLF1 correlates with malignant transformation in human cancer, little is known about how MLF1 is involved in the regulation of cell growth. Here we show that MLF1 is a negative regulator of cell cycle progression functioning upstream of the tumor suppressor p53. MLF1 induces p53-dependent cell cycle arrest in murine embryonic fibroblasts. This action requires a novel binding partner, subunit 3 of the COP9 signalosome (CSN3). A reduction in the level of CSN3 protein with small interfering RNA abrogated MLF1-induced G1 arrest and impaired the activation of p53 by genotoxic stress. Furthermore, ectopic MLF1 expression and CSN3 knockdown inversely affect the endogenous level of COP1, a ubiquitin ligase for p53. Exogenous expression of COP1 overcomes MLF1-induced growth arrest. These results indicate that MLF1 is a critical regulator of p53 and suggest its involvement in leukemogenesis through a novel CSN3-COP1 pathway.