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Cyclin-dependent Kinase Inhibitor p57^KIP2 in Soft Tissue Sarcomas and Wilms' Tumors¹

Memorial Sloan-Kettering Cancer Center [I. O., F. B., E. L., W. L. G., C. C-C.] and Howard Hughes Medical Institute [A. I., M-H., L., J. M.]; New York, New York 10021, and University of North Carolina, Chapel Hill, North Carolina 27599 [S. J. C-M., B. E. W.]

Mammalian cyclin-dependent kinase inhibitors fall into two families, the INK4 and the CIP/KIP. The CIP/KIP family comprises three structurally related members, including p21^CiP1/WAF1, p27^KIP1, and p57^KIP2. These proteins are all capable of inhibiting the progression of the cell cycle by binding and inhibiting G₁ cyclin/cyclin-dependent kinase complexes. In humans, p57^KIP2 is expressed specifically in skeletal muscle, heart, brain, kidney, and lung. Human KIP2 resides in 11p15.5, a chromosomal region that is a common site for loss of heterozygosity in certain sarcomas, Wilms' tumors, and tumors associated with the Beckwith-Wiedemann syndrome. Because of the function, selective expression, and chromosomal location of p57^KIP2, we undertook the present study to search for potential mutations of KIP2 in a cohort of 126 tumors composed of 75 soft tissue sarcomas and 51 Wilms' tumors. The KIP2 gene was characterized by Southern blot, comparative multiplex PCR, PCR-single-strand conformational polymorphism, and DNA sequencing assays in these neoplasms. Deletions of the KIP2 gene or point mutations at the region encoding the cyclin-dependent kinase inhibitory domain were not found in the tumors analyzed. The absence of KIP2 mutations might indicate that these tumors arise due to defects at a closely linked but separate locus. Alternatively, similarly to the mouse homologue, inactivation of KIP2 could occur via genomic imprinting.

¹ This research was supported in part by NIH Grants CA-47538, CA-47179, CA-DK-47650 (C. C-C.), and CA-63196 (B. W.). S. J. C-M. was supported by NIH Predoctoral Training Grant ES07017. J. M. is a Howard Hughes Medical Institute Investigator, and support for this work was provided in part by the Howard Hughes Medical Institute.

² To whom requests for reprints should be addressed, at Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-7746; Fax: (212) 794-3186.

Received 12/12/95. Accepted 1/31/96.

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