Targeted disruption of CDK4 delays cell cycle entry with enhanced p27<SUP>Kip1</SUP> activity

作     者：Tsutsui, T Hesabi, B Moons, DS Pandolfi, PP Hansel, KS Koff, A Kiyokawa, H 

作者机构：Univ Illinois Coll Med Dept Mol Genet Chicago IL 60607 USA Univ Illinois Coll Med Ctr Canc Div Dev Therapeut Chicago IL 60607 USA Mem Sloan Kettering Canc Ctr Dept Human Genet New York NY 10021 USA Mem Sloan Kettering Canc Ctr Program Mol Biol New York NY 10021 USA 

出 版 物：《MOLECULAR AND CELLULAR BIOLOGY》 (分子生物学与细胞生物学)

年 卷 期：1999年第19卷第10期

页      面：7011-7019页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NIGMS NIH HHS [GM52597  R01 GM052597] Funding Source: Medline 

主　　题：萎缩 细胞周期/遗传学 细胞周期蛋白质类 黄体/病理学 细胞周期蛋白依赖激酶4 细胞周期蛋白依赖激酶6 周期素依赖激酶抑制剂p27 细胞周期蛋白质依赖激酶类/遗传学 细胞周期蛋白质依赖激酶类/代谢 糖尿病 糖尿 纯合子 小鼠 突变型 微管相关蛋白质类/遗传学 微管相关蛋白质类/代谢 蛋白质结合 蛋白质丝氨酸苏氨酸激酶/分析 原癌基因蛋白质类 细精管/病理学 组织分布 肿瘤抑制蛋白质类 动物 女(雌)性 男(雄)性 小鼠 

摘      要：The mechanism by which cyclin-dependent kinase 4 (CDK4) regulates cell cycle progression is not entirely clear. Cyclin D/CDK4 appears to initiate phosphorylation of retinoblastoma protein (Rb) leading to inactivation of the S-phase-inhibitory action of Rb. However, cyclin D/CDK4 has been postulated to act in a noncatalytic manner to regulate the cyclin E/CDK2-inhibitory activity of p27(Kip1) by sequestration. In this study we investigated the roles of CDK4 in cell cycle regulation by targeted disruption of the mouse CDK4 gene. CDK4(-/-) mice survived embryogenesis and showed growth retardation and reproductive dysfunction associated with hypoplastic seminiferous tubules in the testis and perturbed corpus luteum formation in the ovary. These phenotypes appear to be opposite to those of p27-deficient mice such as gigantism and gonadal hyperplasia. A majority of CDK4(-/-) mice developed diabetes mellitus by 6 weeks, associated with degeneration of pancreatic islets. Fibroblasts from CDK4(-/-) mouse embryos proliferated similarly to wild-type embryonic fibroblasts under conditions that promote continuous growth. However, quiescent CDK4(-/-) fibroblasts exhibited a substantial (similar to 6-h) delay in S-phase entry after serum stimulation. This cell cycle perturbation by CDK4 disruption was associated with increased binding of p27 to cyclin E/CDK2 and diminished activation of CDK2 accompanied by impaired Rb phosphorylation. Importantly, fibroblasts from CDK4(-/-) p27(-/-) embryos displayed partially restored kinetics of the G(0)-S transition, indicating the significance of the sequestration of p27 by CDK-4. These results suggest that at least part of CDK4 s participation in the rate-limiting mechanism for the G(0)-S transition consists of controlling p27 activity.