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Identification of Functional Elements of p18^INK4C Essential for Binding and Inhibition of Cyclin-dependent Kinase (CDK) 4 and CDK6¹

Department of Biological Chemistry and the Institute of Gerontology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606 [S. J. N., K-L. G.]; and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7295 [Y. L., Y. X.]

Members of the INK4 family of cyclin-dependent kinase (CDK) inhibitors specifically bind and inhibit the G₁-specific CDK molecules CDK4 and CDK6. One of the INK4 molecules, p16, is also known as multiple tumor suppressor and has been found to be mutated or deleted in various tumors and cell lines. We have previously identified p18 as a member of the INK4 family. To determine the molecular basis for the inhibitory function of p18, we introduced 11 missense mutations of conserved residues that were identified in p16 of cancer cell lines into p18. The effects of these mutations on the ability of p18 to bind and inhibit CDK4 and CDK6 or to inhibit cell growth were determined. Our results indicate that the third ankyrin repeat and the NH₂-terminal portion of the fourth repeat constitute the essential element necessary for the ability of p18 to bind and inhibit CDK4 and CDK6. Apart from this core interaction element, p18 seems to use additional, distinct residues to differentially bind and inhibit CDK4 and CDK6, accounting for the known penchant of p18 to preferentially interact with CDK6.

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