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

机译：体内控制细胞增殖的p27（kip1）和stathmin的遗传表征

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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.
机译：CDK抑制剂p27（kip1）是细胞周期进程的关键调节剂，但p27（kip1）控制体内细胞增殖的机制仍未完全阐明。我们最近证明，微管去稳定蛋白stathmin是相关的p27（kip1）结合伴侣。为了深入了解这种相互作用的体内意义，我们产生了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，大多数p27（kip1）无效表型与过度增殖行为有关，例如体重和器官重量增加，视网膜基底层的外生以及垂体腺瘤的发展。 ，通过消融stathmin恢复。体内分析显示，与p27（kip1）空小鼠相比，DKO中DKO的增殖率降低，在分子水平上与CDK4 / 6而不是CDK1和CDK2的激酶活性降低相关。小鼠胸腺的基因表达谱证实了体内观察到的表型，表明DKO与WT的簇集比与p27敲除组织的簇集更多。两者合计，我们的结果表明，stathmin与p27（kip1）协同控制G1到S相过渡的早期阶段，并且该功能在肿瘤进展的背景下可能特别相关。

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