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ROLE OF THE CDK INHIBITOR IN BONE FORMATION AND METABOLISM

CDK 抑制剂在骨形成和代谢中的作用

基本信息

批准号：
13671173
负责人：
TOYOSHIMA Hideo
金额：
$ 2.62万
依托单位：
UNIVERSITY OF TSUKUBA
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671173/
关键词：
CDK inhibitor p57Kip2 LIM-kinase osteoblast differentiation actin dynamics 細胞周期 CDK サイクリン LIM kinase 骨形成骨代謝 Cdk阻害因子

项目摘要

G1 cyclin / CDK complexes play essential roles for the progression of the cell cycle from G1 phase to S phase. RB tumor suppressor is one of the important target of G1 cyclin / CDKs, and CDK inhibitors (CK1), which negatively regulates there activity has been shown to be involved in the regulation of oncogenesis and differentiation. We have been investigating the regulation of cell differentiation process by the p27 CDK inhibitor and a related gene, p57, and have recently shown that p57 may play an essential role in osteoblastic cell differentiation process. p57^<Kip2> is the only Cdk inhibitor that has been shown to be essential for mouse embryogenesis. The fact suggested that p57 may have a specific role that cannot be compensated by other CKIs. In our study, we demonstrate that p57 regulates actin dynamics through binding to LIM-kinase 1 (LIMK-1). The central region of p57, a unique feature among the CKIs, and the N-terminal region of LIMK-1, which contains the LIM domains were essential for this interaction. Binding of p57 did not show significant inhibition of the LIMK-1 activity to phosphorylate cofilin. However, overexpression of p57, but neither p27^<Kip1> nor a p57 mutant with a deletion in its unique central region, was shown to induce a marked translocation of LIMK-1 from the cytoplasms into the nucleus, and the reorganization of actin filament in the cytoplasms. These results indicate that p57 bear two distinct functions, the regulation of cell cycle through binding to Cdks, and the regulation of actin dynamics through binding to LIMK-1, both of which should be important in developmental procedure.

G1期细胞周期蛋白/ CDK复合物在细胞周期从G1期进入S期过程中发挥着重要作用。RB肿瘤抑制因子是G1期细胞周期蛋白/ CDKs的重要靶点之一，CDK抑制因子（CK 1）负性调节其活性，参与肿瘤的发生和分化。我们一直在研究p27 CDK抑制剂和相关基因p57对细胞分化过程的调节，最近发现p57可能在成骨细胞分化过程中起重要作用。p57 β<Kip2>是唯一的Cdk抑制剂，已被证明是必要的小鼠胚胎发生。事实表明，p57可能具有其他CKI无法补偿的特定作用。在我们的研究中，我们证明了p57通过与LIMK-1结合来调节肌动蛋白动力学。p57的中心区域，CKI中的独特特征，以及LIMK-1的N-末端区域，其包含LIM结构域，对于这种相互作用是必需的。p57的结合没有显示出对LIMK-1磷酸化cofilin的活性的显著抑制。然而，p57的过表达，而不是p27或<Kip1>在其独特的中心区域缺失的p57突变体，显示出诱导LIMK-1从细胞壁显著移位到细胞核中，以及细胞壁中肌动蛋白丝的重组。这些结果表明，p57承担两个不同的功能，通过结合Cdks的细胞周期的调节，并通过结合LIMK-1的肌动蛋白动力学的调节，这两个应该是重要的发育过程中。