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p27(kip1)和Stathmin在体内控制细胞增殖中的遗传学特征

Genetic characterization of p27(kip1) and stathmin in controlling cell proliferation in vivo.

作者信息

Berton Stefania, Pellizzari Ilenia, Fabris Linda, D'Andrea Sara, Segatto Ilenia, Canzonieri Vincenzo, Marconi Daniela, Schiappacassi Monica, Benevol Sara, Gattei Valter, Colombatti Alfonso, Belletti Barbara, Baldassarre Gustavo

机构信息

a Department of Translational Research; Division of Experimental Oncology 2; CRO of Aviano, National Cancer Institute ; Aviano , Italy.

出版信息

Cell Cycle. 2014;13(19):3100-11. doi: 10.4161/15384101.2014.949512.

Abstract

The CDK inhibitor p27(kip1) is a critical regulator of cell cycle progression, but the mechanisms by which p27(kip1) controls cell proliferation in vivo are still not fully elucidated. We recently demonstrated that the microtubule destabilizing protein stathmin is a relevant p27(kip1) binding partner. To get more insights into the in vivo significance of this interaction, we generated p27(kip1) and stathmin double knock-out (DKO) mice. Interestingly, thorough characterization of DKO mice demonstrated that most of the phenotypes of p27(kip1) null mice linked to the hyper-proliferative behavior, such as the increased body and organ weight, the outgrowth of the retina basal layer and the development of pituitary adenomas, were reverted by co-ablation of stathmin. In vivo analyses showed a reduced proliferation rate in DKO compared to p27(kip1) null mice, linked, at molecular level, to decreased kinase activity of CDK4/6, rather than of CDK1 and CDK2. Gene expression profiling of mouse thymuses confirmed the phenotypes observed in vivo, showing that DKO clustered with WT more than with p27 knock-out tissue. Taken together, our results demonstrate that stathmin cooperates with p27(kip1) to control the early phase of G1 to S phase transition and that this function may be of particular relevance in the context of tumor progression.

摘要

细胞周期蛋白依赖性激酶(CDK)抑制剂p27(kip1)是细胞周期进程的关键调节因子,但p27(kip1)在体内控制细胞增殖的机制仍未完全阐明。我们最近证明,微管解聚蛋白stathmin是一种与p27(kip1)相关的结合伴侣。为了更深入了解这种相互作用在体内的意义,我们构建了p27(kip1)和stathmin双敲除(DKO)小鼠。有趣的是,对DKO小鼠的全面表征表明,p27(kip1)基因敲除小鼠的大多数与过度增殖行为相关的表型,如体重和器官重量增加、视网膜基底层生长以及垂体腺瘤的发生,都通过stathmin的共同消融而恢复。体内分析显示,与p27(kip1)基因敲除小鼠相比,DKO小鼠的增殖率降低,在分子水平上,这与CDK4/6激酶活性降低有关,而不是与CDK1和CDK2有关。小鼠胸腺的基因表达谱分析证实了体内观察到的表型,表明DKO与野生型(WT)的聚类比与p27基因敲除组织的聚类更相似。综上所述,我们的结果表明,stathmin与p27(kip1)协同作用以控制G1期到S期转换的早期阶段,并且这种功能在肿瘤进展的背景下可能具有特别重要的意义。

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