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p16^Ink4a Tumor Suppressor Function in Lung Cancer Cells Involves Cyclin-dependent Kinase 2 Inhibition by Cip/Kip Protein Redistribution¹

University of Colorado Comprehensive Cancer Center and Department of Biochemistry and Molecular Genetics [B. G., R. A. S.] and Department of Pharmacology [T. A. L.], University of Colorado Health Sciences Center, Denver, Colorado 80262

Abstract

As cell cycle regulators whose activity is frequently altered in human cancers, cyclin-dependent kinases (cdks) are novel targets for therapeutic intervention. cdk inhibition is an emerging strategy for the treatment of non-small cell lung carcinomas (NSCLCs) because most derived cell lines express functional retinoblastoma protein (Rb) but appear to bypass its function with inappropriate cdk activity. Elevated cdk4/cdk6 activity in NSCLC cells is often due to inactivation of the p16^Ink4a cdk inhibitor. To model the effects of cdk4/cdk6 inhibition, we have expressed p16^Ink4a in a Rb-positive NSCLC cell line that lacks endogenous p16^Ink4a expression. Whereas cdk4/cdk6 inhibition and Rb dephosphorylation are expected on p16^Ink4a expression, we have also observed indirect cdk2 inhibition. cdk2 inactivation by the redistribution of other cdk inhibitors may be required for p16^Ink4a-mediated growth suppression of Rb-positive cells. The implications of such a requirement on the use of chemical cdk inhibitors to treat human cancers will be discussed.

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