P57(KIP2), A STRUCTURALLY DISTINCT MEMBER OF THE P21(CIP1) CDK INHIBITOR FAMILY, IS A CANDIDATE TUMOR-SUPPRESSOR GENE

Cydin-dependent kinases (Cdks) are positive regulators of cell proliferation, whereas Cdk inhibitors (CKIs) inhibit proliferation. We describe a new CKI, p57(KIP2), which is related to p21(CIP1) and p27(KIP1). p57(KIP2) is a potent, tight-binding inhibitor of several G(1) cyclin/Cdk complexes, and its binding is cyclin dependent. Unlike CIP1, KIP2 is not regulated by p53. Overexpression of p57(KIP2) arrests cells in G(1). p57(KIP2) proteins have a complex structure. Mouse p57(KIP2) consists Of four structurally distinct domains: an amino-terminal Cdk inhibitory domain, a proline-rich domain, an acidic-repeat region, and a carboxy-terminal domain conserved with p27(KIP1). Human p57(KIP2) appears to have conserved the amino- and carboxy-terminal domains but has replaced the internal regions with sequences containing proline-alanine repeats. In situ hybridization during mouse embryogenesis revealed that KIP2 mRNA displays a striking pattern of expression during development, showing high level expression in skeletal muscle, brain, heart, lungs, and eye. Most of the KIP2-expressing cells are terminally differentiated, suggesting that p57(KIP2) is involved in decisions to exit the cell cycle during development and differentiation. Human KIP2 is located at 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome, marking it as a candidate tumor suppressor. The discovery of a new member of the p21(CIP1) inhibitor family with novel structural features and expression patterns suggests a complex role for these proteins in cell cycle control and development.