Cks1 Promotion of S Phase Entry and Proliferation Is Independent of p27Kip1 Suppression
Cks1 Promotion of S Phase Entry and Proliferation Is Independent of p27Kip1 Suppression
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DOI：
10.1128/mcb.06771-11
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发表时间：
2012-07-01
影响因子：
5.3
通讯作者：
Keller, Ulrich
中科院分区：
文献类型：
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作者：
Hoellein, Alexander;Graf, Steffi;Keller, Ulrich
Cks 1是SCFSkp 2泛素连接酶复合物的激活剂，靶向细胞周期抑制剂p27（Kip 1）进行降解。Cks 1的缺失导致p27（Kip 1）积累和增殖降低并抑制肿瘤发生。我们在这里确定的CKS 1在哺乳动物细胞周期调控的功能是独立的p27（Kip 1）。具体而言，Cks 1（-/-）; p27（Kip 1-/-）小鼠胚胎成纤维细胞保留了G（1）-S相变中的缺陷，这与Cdk 2相关激酶活性降低和与Cks 1丢失相关的增殖缺陷相结合。此外，伴随的Cks 1的缺失不能挽救p27（Kip 1）的肿瘤抑制功能，其在p27（Kip 1-/-）小鼠的各种器官中表现出来。相反，有丝分裂进入缺陷和Cks 1（-/-）细胞中表现出的过早衰老是p271（Kip 1）依赖的。总的来说，这些发现确立了Cks 1在调节G（1）-S转换中的p27（Kip 1）独立功能。
Cks1 is an activator of the SCFSkp2 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 p271(Kip1) dependent. Collectively, these findings establish p27(Kip1)-independent functions of Cks1 in regulating the G(1)-S transition.