ROLE OF THE CDK INHIBITOR IN BONE FORMATION AND METABOLISM

G1周期蛋白/ CDK复合物在细胞周期从G1期向S期的进展中起着重要作用。RB肿瘤抑制因子是G1 cyclin / CDKs的重要靶点之一，而CDK抑制剂（CK1）负调控其活性已被证明参与肿瘤发生和分化的调控。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控，最近发现p57可能在成骨细胞分化过程中发挥重要作用。p57^<Kip2>是唯一被证明对小鼠胚胎发生至关重要的Cdk抑制剂。这一事实表明p57可能具有其他CKIs无法弥补的特殊作用。在我们的研究中，我们证明p57通过与LIMK-1 （LIMK-1）结合来调节肌动蛋白动力学。p57的中心区域（CKIs中一个独特的特征）和LIMK-1的n端区域（包含LIM结构域）对于这种相互作用至关重要。p57的结合对LIMK-1磷酸化cofilin的活性没有明显的抑制作用。然而，p57的过表达，而不是p27^<Kip1>，也不是p57在其独特的中心区域缺失的突变体，诱导了LIMK-1从细胞质到细胞核的明显易位，以及细胞质中肌动蛋白丝的重组。这些结果表明p57具有两种不同的功能，通过与Cdks结合来调节细胞周期，以及通过与LIMK-1结合来调节肌动蛋白动力学，这两种功能在发育过程中都应该是重要的。

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.