CYCLIN-DEPENDENT KINASE INHIBITOR P57(KIP2) IN SOFT-TISSUE SARCOMAS AND WILMS-TUMORS

Mammalian cyclin-dependent kinase inhibitors fall into two families, t he INK4 and the CIP/KIP. The CIP/KIP family comprises three structural ly related members, including p21(CiP/WAF1), p27(KIP1), and p57(KIP2). These proteins are all capable of inhibiting the progression of the c ell cycle by binding and inhibiting G(1) cyclin/cyclin-dependent kinas e complexes. In humans, p57(KIP2) is expressed specifically in skeleta l muscle, heart, brain, kidney, and lung. Human KIP2 resides in 11p15. 5, a chromosomal region that is a common site for loss of heterozygosi ty in certain sarcomas, Wilms' tumors, and tumors associated with the Beckwith-Wiedemann syndrome. Because of the function, selective expres sion, and chromosomal location of p57(KIP2), we undertook the present study to search for potential mutations of KIP2 in a cohort of 126 tum ors composed of 75 soft tissue sarcomas and 51 Wilms' tumors. The KIP2 gene was characterized by Southern blot, comparative multiplex PCR, P CR-single-strand conformational polymorphism, and DNA sequencing assay s in these neoplasms. Deletions of the KIP2 gene or point mutations at the region encoding the cyclin-dependent kinase inhibitory domain wer e not found in the tumors analyzed. The absence of KIP2 mutations migh t indicate that these tumors arise due to defects at a closely Linked but separate locus. Alternatively, similarly to the mouse homologue, i nactivation of KIP2 could occur via genomic imprinting.