Depletion of CSN5 inhibits Ras-mediated tumorigenesis by inducing premature senescence in p53-null cells
Depletion of CSN5 inhibits Ras-mediated tumorigenesis by inducing premature senescence in p53-null cells
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CSN5 的缺失通过诱导 p53 缺失细胞过早衰老来抑制 Ras 介导的肿瘤发生
DOI：
10.1016/j.febslet.2012.10.042
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发表时间：
2012
期刊：
影响因子：
3.5
通讯作者：
Kato JY
中科院分区：
文献类型：
--
作者：
Tsujimoto I;Yoshida A;Yoneda-Kato N;Kato JY
哺乳动物COP 9信号体（CSN）复合物参与细胞转化，但其分子机制尚未确定。在这里，我们表明，破坏的第五个组成部分（CSN 5）防止肿瘤形成的p53-null细胞转化的活性形式的Ras在皮下注射小鼠。CSN 5的耗尽抑制细胞增殖，并诱导以衰老相关β-半乳糖苷酶活性上调和CDK抑制剂表达增加为特征的过早衰老。CSN 5耗尽的细胞表现出增强的PI 3激酶-Akt通路的活化，并且该通路的化学抑制降低了衰老水平。因此，CSN 5被认为是癌症治疗和针对携带突变p53的肿瘤细胞的药物的新靶点。
The mammalian COP9 signalosome (CSN) complex is involved in cell transformation, but its molecular mechanism remains undetermined. Here we show that disruption of the fifth component (CSN5) prevented the formation of tumors by p53-null cells transformed with an active form of Ras in subcutaneously injected mice. Depletion of CSN5 suppressed cell proliferation, and induced premature senescence characterized by upregulation of senescence-associated-β-galactosidase activity and increased expression of CDK inhibitors. CSN5-depleted cells exhibited enhanced activation of the PI3 kinase–Akt pathway, and chemical inhibition of this pathway reduced the level of senescence. Thus, CSN5 is suggested to be a novel target in cancer therapy and for drugs against tumor cells harboring mutated p53.