The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation.
The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation.
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DOI：
10.1038/onc.2012.182
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发表时间：
2013-03-28
期刊：
影响因子：
8
通讯作者：
Gopalakrishnan, V.
中科院分区：
文献类型：
--
作者：
Das, C. M.;Taylor, P.;Gireud, M.;Singh, A.;Lee, D.;Fuller, G.;Ji, L.;Fangusaro, J.;Rajaram, V.;Goldman, S.;Eberhart, C.;Gopalakrishnan, V.
RE 1沉默转录因子（REST）是神经元分化的阻遏物，其在神经细胞中的表达升高阻断神经元分化。在本研究中，我们证明了REST在控制髓母细胞瘤细胞增殖中的作用。REST表达降低了CDKNIB/p27的水平，CDKNIB/p27是一种细胞周期蛋白依赖性激酶抑制剂，也是这些细胞中细胞增殖的制动器。REST和p27之间的相互关系在人类肿瘤样品中得到验证。髓母细胞瘤细胞中REST敲除破坏了编码去泛素化酶泛素特异性肽酶37（USP 37）的新型REST靶基因。异位表达的野生型USP 37与p27形成复合物，促进其去泛素化和稳定化，并阻断细胞增殖。REST和USP 37的敲除阻止了p27的稳定，并阻止了通常伴随REST丧失的增殖潜力的降低。出乎意料的是，野生型USP 37表达也诱导REST靶向神经元分化基因的表达，即使REST水平不受影响。相反，在保守的半胱氨酸中携带定点改变的USP 37突变体未能挽救REST介导的p27不稳定，维持细胞增殖和阻断神经元分化。与这些发现一致，在患者肿瘤中观察到USP 37和p27之间的显著相关性。总的来说，这些发现提供了一个新的REST和蛋白酶体机制之间的联系，在髓母细胞瘤细胞的p27和细胞增殖的控制。
The RE1 Silencing Transcription Factor (REST) is a repressor of neuronal differentiation and its elevated expression in neural cells blocks neuronal differentiation. In the present study, we demonstrate a role for REST in the control of proliferation of medulloblastoma cells. REST expression decreased the levels of CDKNIB/p27, a cyclin-dependent kinase inhibitor and a brake of cell proliferation in these cells. The reciprocal relationship between REST and p27 was validated in human tumor samples. REST knockdown in medulloblastoma cells derepessed a novel REST-target gene encoding the deubiquitylase ubiquitin-specific peptidase 37 (USP37). Ectopically expressed wild type USP37 formed a complex with p27, promoted its deubiquitination and stabilization and blocked cell proliferation. Knockdown of REST and USP37 prevented p27 stabilization and blocked the diminution in proliferative potential that normally accompanied REST loss. Unexpectedly, wild type USP37 expression also induced the expression of REST-target neuronal differentiation genes even though REST levels were unaffected. In contrast, a mutant of USP37 carrying a site-directed change in a conserved cysteine failed to rescue REST-mediated p27 destabilization, maintenance of cell proliferation and blockade to neuronal differentiation. Consistent with these findings, a significant correlation between USP37 and p27 was observed in patient tumors. Collectively, these findings provide a novel connection between REST and the proteasomal machinery in the control of p27 and cell proliferation in medulloblastoma cells.
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影响因子：
3.7
作者：
Abrajano JJ;Qureshi IA;Gokhan S;Zheng D;Bergman A;Mehler MF
通讯作者：
Mehler MF
影响因子：
1.3
作者：
Gopalakrishnan V
通讯作者：
Gopalakrishnan V
影响因子：
21.3
作者：
Carrano, AC;Eytan, E;Pagano, M
通讯作者：
Pagano, M
DOI：
10.1073/pnas.0401827101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Bruce, AW;Donaldson, IJ;Buckley, NJ
通讯作者：
Buckley, NJ
影响因子：
64.5
作者：
CHONG, JHA;TAPIARAMIREZ, J;MANDEL, G
通讯作者：
MANDEL, G