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Differential Expression and Cell Cycle Regulation of the Cyclin-dependent Kinase 4 Inhibitor p16^Ink4

Mitotix, Inc., Cambridge, Massachusetts 02139 [S. W. T., M. P.], and the Department of Cell Biology and Neurosciences, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235 [J. W. S.]

p16^Ink4 (inhibitor of cyclin-dependent kinase 4) is a cell cycle regulator that specifically binds to and inhibits Cdk4. Recently, the human mts1 (multiple tumor suppressor 1) gene, deleted or mutated in various primary tumors and in a large number of transformed cell lines, was found to be identical to ink4. In this study we have surveyed by immunoblotting the protein levels of p16^Ink4 in normal and transformed human cells. We determined that p16^Ink4 was differentially expressed in diploid cells derived from different tissues, in contrast to another cell cycle inhibitor, p21^Waf1, which is ubiquitously expressed. In some tumor cell lines p16^Ink4 protein was not detected, presumably because of a homozygous deletion of its gene. By contrast, it was found to be overexpressed in other cell lines when compared to levels in their normal counterparts. Interestingly, high levels of p16^Ink4 protein correlated with functional inactivation of the retinoblastoma gene product. We also found that p16^Ink4 protein expression varies during the cell cycle peaking during S phase. These results show a functional relationship between p16^Ink4 and the retinoblastoma gene product and indicate that p16^Ink4 is required for Cdk4 inhibition only at the G₁-S transition at the time when Cdk4 kinase activity is no longer necessary.

¹ Supported in part by the Human Science Frontier Program Grant RG-496/93.

² Supported in part by the NIH Grant CA50195 and the Susan G. Komen Breast Cancer Foundation.

³ To whom requests for reprints should be addressed.

Received 9/ 2/94. Accepted 10/ 5/94.

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