The RASSF1A tumor suppressor restrains anaphase-promoting complex/cyclosome activity during the G1/S phase transition to promote cell cycle progression in human epithelial cells.
The RASSF1A tumor suppressor restrains anaphase-promoting complex/cyclosome activity during the G1/S phase transition to promote cell cycle progression in human epithelial cells.
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RASSF1A 肿瘤抑制因子在 G1/S 相转变期间抑制后期促进复合物/环小体活性，以促进人上皮细胞的细胞周期进程。
DOI：
10.1128/mcb.02291-07
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发表时间：
2008
影响因子：
5.3
通讯作者：
White,MichaelA
中科院分区：
文献类型：
--
作者：
Whitehurst,AngeliqueW;Ram,Rosalyn;Shivakumar,Latha;Gao,Boning;Minna,JohnD;White,MichaelA
人类癌症中的多个分子病变直接协作，解除对增殖的调控，抑制细胞凋亡，促进肿瘤的发生。候选肿瘤抑制基因RASSF1A通常在人类多种肿瘤中失活，并被认为是细胞周期进程的关键守门人。然而，RASSF1A基因失活在肿瘤发生中的作用缺乏机制的解释。在这里，我们使用了人上皮细胞的功能丧失分析来详细研究RASSF1对细胞周期进程的贡献。我们发现RASSF1a与G1/S期细胞周期传递具有双向相反的调控联系。RASSF1A与尤文肉瘤断裂点蛋白EWS结合，以限制细胞周期蛋白D1的积聚，并限制从G1退出。令人惊讶的是，我们发现RASSF1A还需要限制SCFβTrCP的活性，以允许G/S相变。这种限制对于后期促进复合体/环体(APC/C)抑制剂Emi1的积累和伴随的APC/C依赖的Cyclin A转换的阻断是必需的。这种关系的结果是，尽管细胞周期蛋白D1浓度升高，但在RASSF1A耗尽时，正常上皮细胞的细胞周期进程受到抑制。因此，在RASSF1a基因失活后进展为致瘤性需要协同遗传异常，从而绕过G1/S期细胞周期转变中APC/C调节受损的后果。
Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G1/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G1. Surprisingly, we found that RASSF1A is also required to restrict SCFβTrCPactivity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G1/S phase cell cycle transition.