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Increased p16 Levels Correlate with pRb Alterations in Human Urothelial Cells¹

Department of Human Oncology, University of Wisconsin Medical School, Madison, Wisconsin 53792 [T. Y., C. B., J. P., C. R.], and Department of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637 [W. S., O. O.]

The CDKN2 (MTS1) gene is located at 9p21; its product, p16, inhibits the cyclin D/CDK4 complex that phosphorylates pRb, thus negatively regulating cell cycle progression [M. Serrano et al., Nature (Lond.), 366: 704, 1994; A. Kamb et al., Science (Washington DC), 264: 436, 1994; T. Nobori et al., Nature (Lond.), 368: 753, 1994]. CDKN2 mutations are more common in cultured human uroepithelial cells (HUC) than in uncultured bladder cancers. We examined the status of CDKN2/p16 in early and late passage (P) cultures of HUC. HUC immortalization was not accompanied by p16 loss, even in cells with a hemizygous 9p21-pter deletion, but late passage cultures with a p16 loss showed decreased generation time. Thus, the data do not indicate that CDKN2 is a candidate for a chromosome 9 senescence gene but suggest that p16 loss may confer a growth advantage in vitro. Significant differences in p16 levels were observed among HUC cell lines, but no CDKN2 mutations were detected. However, an inverse correlation between elevated p16 and loss of pRb function was observed (P < 10^-4). Ten samples with normal pRb showed low or undetectable p16 levels, while seven samples with known pRb alterations showed abundant p16 but nevertheless grew vigorously in culture. These results support the hypothesis that p16 mediated cell cycle inhibition, as well as p16 regulation, occurs via pRb dependent pathway(s).

¹ Supported by NIH CA-29525-15 to C. R.; ACS PRTA 22, ASCO young Investigator award, and a James S. McDonnel Foundation Award #92-51 to W. S.; and NIH training grant (T32E507015) to the Cell and Molecular Biology Program at UW-Madison for T. Y.

² These authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at K4/562 CSC, 600 Highland Ave., Madison, WI 53792.

Received 11/11/94. Accepted 12/19/94.

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