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JNCI Journal of the National Cancer Institute 1999 91(18):1569-1574; doi:10.1093/jnci/91.18.1569
© 1999 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 91, No. 18, 1569-1574, September 15, 1999
© 1999 Oxford University Press

REPORTS

Biologic and Biochemical Analyses of p16INK4a Mutations From Primary Tumors

Wendell G. Yarbrough, Robert A. Buckmire, Mika Bessho, Edison T. Liu

Affiliations of authors: W. G. Yarbrough (Department of Surgery, Division of Otolaryngology/Lineberger Comprehensive Cancer Center), R. A. Buckmire (Department of Surgery, Division of Otolaryngology), M. Bessho (Lineberger Comprehensive Cancer Center), University of North Carolina at Chapel Hill; E. T. Liu, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD.

Correspondence to: Wendell G. Yarbrough, M.D., University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, CB#7295, Chapel Hill, NC 27599-7295 (e-mail: wgy{at}med.unc.edu).

BACKGROUND: Point mutations in the tumor suppressor gene p16INK4a (also known as p16, CDKN2, MTS1, and INK4a) are found in many tumor types. Because the function of the products of these naturally occurring mutants has not been fully explored, we investigated the functional activities of a wide range of naturally occurring p16 mutant proteins. METHODS: Sixteen cancer-associated p16 mutant proteins, resulting from missense mutations, were characterized for their ability to bind and inhibit the cyclin-dependent kinases (CDK4 and CDK6) and to induce cell cycle arrest in G1 phase. RESULTS/CONCLUSIONS: Among 16 mutants analyzed, nine had detectable functional defects. Three mutants (D84V, D84G, and R87P) had defects in CDK binding, kinase inhibition, and cell cycle arrest. The corresponding mutations are located in the third ankyrin repeat in a highly conserved region believed to form the CDK binding cleft. Three mutants (P48L, D74N, and R87L) had defects in kinase inhibition and cell cycle arrest. Among the 10 mutants with normal CDK binding and inhibitory activity, three mutants (N71S, R80L, and H83Y) had defects only in their ability to induce cell cycle arrest. Thus, p16 mutant proteins that retain CDK4 and CDK6 binding may have more subtle functional defects. All nine mutations leading to functional impairments mapped to the central portion of the p16 protein. Ankyrin repeats II and III appear more critical to p16 function, and mutations in ankyrin repeats I and IV are less likely to disrupt p16 function.


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