GSK-3β targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3β inactivation correlates with Cdc25A overproduction in human cancers
GSK-3β targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3β inactivation correlates with Cdc25A overproduction in human cancers
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DOI：
10.1016/j.ccr.2007.12.002
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发表时间：
2008-01-01
期刊：
影响因子：
50.3
通讯作者：
Piwnica-Worms, Helen
中科院分区：
文献类型：
--
作者：
Kang, Tiebang;Wei, Yongkun;Piwnica-Worms, Helen
Cdc 25 A磷酸酶积极调节细胞周期转换，在整个间期和应激反应中被蛋白体降解，并且在人类癌症中过量产生。针对Cdc 25 A的激酶在早期细胞周期阶段的蛋白水解尚未确定，并在人类癌症中的Cdc 25 A过度生产的原因缺乏机制的见解。在这里，我们证明了糖原合成酶激酶-3 β（GSK-3 β）磷酸化Cdc 25 A，以促进其在细胞周期早期阶段的蛋白水解。GSK-3 β的磷酸化需要Cdc 25 A的引发，并且这可以由polo样激酶3（PIk-3）催化。重要的是，在人类肿瘤组织中观察到Cdc 25 A过度产生和GSK-3 β失活之间的强相关性，表明GSK-3 β失活可能是人类肿瘤亚组中Cdc 25 A过度产生的原因。
The Cdc25A phosphatase positively regulates cell-cycle transitions, is degraded by the proteosome throughout interphase and in response to stress, and is overproduced in human cancers. The kinases targeting Cdc25A for proteolysis during early cell-cycle phases have not been identified, and mechanistic insight into the cause of Cdc25A overproduction in human cancers is lacking. Here, we demonstrate that glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylates Cdc25A to promote its proteolysis in early cell-cycle phases. Phosphorylation by GSK-3 beta requires priming of Cdc25A, and this can be catalyzed by polo-like kinase 3 (PIk-3). Importantly, a strong correlation between Cdc25A overproduction and GSK-3 beta inactivation was observed in human tumor tissues, indicating that GSK-3 beta inactivation may account for Cdc25A overproduction in a subset of human tumors.