Cks1 促进 S 期进入和增殖与抑制 p27Kip1 无关。
Cks1 promotion of S phase entry and proliferation is independent of p27Kip1 suppression.
机构信息
Medical Department III, Technische Universität München, Munich, Germany.
出版信息
Mol Cell Biol. 2012 Jul;32(13):2416-27. doi: 10.1128/MCB.06771-11. Epub 2012 Apr 16.
Abstract
Cks1 is an activator of the SCF(Skp2) ubiquitin ligase complex that targets the cell cycle inhibitor p27(Kip1) for degradation. The loss of Cks1 results in p27(Kip1) accumulation and decreased proliferation and inhibits tumorigenesis. We identify here a function of Cks1 in mammalian cell cycle regulation that is independent of p27(Kip1). Specifically, Cks1(-/-); p27(Kip1-/-) mouse embryonic fibroblasts retain defects in the G(1)-S phase transition that are coupled with decreased Cdk2-associated kinase activity and defects in proliferation that are associated with Cks1 loss. Furthermore, concomitant loss of Cks1 does not rescue the tumor suppressor function of p27(Kip1) that is manifest in various organs of p27(Kip1-/-) mice. In contrast, defects in mitotic entry and premature senescence manifest in Cks1(-/-) cells are p27(Kip1) dependent. Collectively, these findings establish p27(Kip1)-independent functions of Cks1 in regulating the G(1)-S transition.
摘要
Cks1 是 Skp2 泛素连接酶复合物的激活因子，可将细胞周期抑制剂 p27(Kip1) 靶向降解。Cks1 的缺失导致 p27(Kip1)积累，增殖减少，并抑制肿瘤发生。我们在这里确定了 Cks1 在哺乳动物细胞周期调控中的一个独立于 p27(Kip1)的功能。具体来说，Cks1(-/-);p27(Kip1-/-) 小鼠胚胎成纤维细胞保留 G1-S 期转换缺陷，与 Cdk2 相关激酶活性降低以及与 Cks1 缺失相关的增殖缺陷有关。此外，同时缺失 Cks1 不能挽救 p27(Kip1)的肿瘤抑制功能，该功能在 p27(Kip1-/-)小鼠的各种器官中表现出来。相比之下，Cks1(-/-)细胞中出现的有丝分裂进入和过早衰老缺陷依赖于 p27(Kip1)。总之，这些发现确立了 Cks1 在调节 G1-S 转换中的 p27(Kip1)非依赖性功能。
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