Cip/Kip proteins: more than just CDKs inhibitors

  1. Catherine Denicourt and
  2. Steven F. Dowdy1
  1. Howard Hughes Medical Institute, and Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, California 92093-0686, USA

This extract was created in the absence of an abstract.

Members of the Cip/Kip family of cyclin-dependent kinases inhibitors (CKIs) are well characterized for their role as negative regulators of G1-phase cell-cycle progression (Sherr and Roberts 1999). In eukaryotic cells, progression through the cell cycle is governed by a suite of cyclins and cyclin-dependent kinase (CDKs) complexes (Murray 2004). Regulation of cyclin–CDKs complexes occurs at multiple levels, including assembly of cyclin and CDK subunits, inhibitory and activating phosphorylation and dephosphorylation events, and association of cyclin–CDK complexes with CKIs. During these regulatory processes, cyclin–CDK complexes positively drive progression of the cell cycle, whereas by binding to and inactivating cyclin–CDKs, CKIs negatively regulate progression through the cell cycle. Based on their sequence homology and specificity of action, CKIs are divided into two distinct families: INK4 and Cip/Kip (Sherr and Roberts 1999). Members of the INK4 family, namely p15, p16, p18, and p19 specifically inhibit the activity of CDK4 and CDK6, whereas Cip/Kip members, that is, p21, p27, and p57 inhibit a broader spectrum of cyclin–CDK complexes (el-Deiry et al. 1993; Gu et al. 1993; Harper et al. 1993; Polyak et al. 1994; Toyoshima and Hunter 1994; Lee et al. 1995).

Until recently, Cip/Kip members were almost solely viewed as nuclear proteins with a principal function of inhibiting cyclin–CDK activity and hence, cell-cycle progression. However, emerging studies now suggest that Cip/Kip proteins play additional roles outside of the nucleus (Coqueret 2003). Indeed, previous reports have linked p27kip1 to the regulation of actin dynamics and cell migration (Nagahara et al. 1998; McAllister et al. 2003). Moreover, several recent papers have shown that p21cip1 can act as a Rho-kinase (ROCK) inhibitor and that p57kip2 modulates subcellular localization of LIMK, a serine/threonine kinase involved in the regulation of actin filaments (Tanaka et al. 2002 …

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