ROLE OF THE CDK INHIBITOR IN BONE FORMATION AND METABOLISM

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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.