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Mutational Effects on the p16^INK4a Tumor Suppressor Protein¹

Division of Hematology/Oncology, University of California at Los Angeles School of Medicine, Cedars-Sinai Research Institute, Los Angeles, California 90048 [R. Y., A. F. G., H. P. K.], and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 [M. S.]

Several point mutations of p16^INK4a were studied by site-specific mutagenesis and functional analysis to assess the effects of these mutations on the function of the protein. These mutations were reported in several malignancies. Three deletional mutants of p16^INK4a were also analyzed to reveal the relationship between p16^INK4a and p15^INK4b and to test the importance of the ankyrin repeats observed in both proteins. We studied the activity of these mutants using the yeast two-hybrid system and an in vitro kinase assay. Our results suggest that point mutations in the conserved ankyrin consensus affect the activity of p16^INK4a. However, not all of the point mutations observed in tumors have a detectable effect on the activity. The COOH-terminal region of p16^INK4a is not required for the protein to bind and to inhibit CDK4, but the deletion of the 4th ankyrin repeat abolished the activity completely.

¹ This research is supported by NIH Grants CA 42710, DK 42792, and CA 26038; the Parker Hughes Trust; the Concern Foundation; and the Louis Shushan Fund. H. P. K. is a member of the Jonsson Cancer Center.

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048.

Received 2/16/95. Accepted 5/ 5/95.

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