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Deletion and Altered Regulation of p16^INK4a and p15^INK4b in Undifferentiated Mouse Skin Tumors¹

Cancer Research Campaign Beatson Laboratories, University of Glasgow, Department of Medical Oncology, and Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom [S. L., A. J. S., A. B.]; Howard Hughes Medical Institute, Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 [D. E. Q., C. J. S.]; and Imperial Cancer Research Fund, Laboratory of Molecular Oncology, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom [D. P., G. P.]

p16^INK4a and p15^INK4b are cell cycle regulators that specifically bind to and inhibit the cyclin D-dependent kinases, cdk4 and cdk6. Because these genes undergo frequent deletions and/or mutations in various human cancers, we examined the status and expression of the cognate mouse cdk inhibitors in a panel of 29 cell lines, as well as in 12 primary tumors, representing different stages of mouse skin carcinogenesis. Deletion of p16^INK4a and/or p15^INK4b was seen in 8 of 10 cell lines derived from spindle carcinomas, the most advanced stage of skin carcinogenesis. Five showed deletion of both genes, and three had independent deletions of p16^INK4a or p15^INK4b, but in those retaining p16^INK4a, expression of the protein was not detected. By contrast, none of 19 more differentiated squamous cell lines exhibited such deletions. In several cases, primary tumor DNA was available, and two spindle tumors showed the same deletion pattern as observed in the corresponding cell lines. In apparent contrast, comparison of two clonally related squamous and spindle cell lines derived from a single carcinoma showed unusually high levels of p16^INK4a and p15^INK4b only in the invasive spindle cells. Therefore, deletion or altered regulation of p16^INK4a and p15^INK4b occur concomitantly with the loss of differentiation associated with the late spindle stage of tumor progression in mouse skin.

¹ This work was supported by the Cancer Research Campaign, the United Kingdom Coordinating Committee for Cancer Research (to S. L.), and the West of Scotland Ladies Bowling Association Fellowship (to A. J. S.).

² To whom requests for reprints should be addressed. Phone: 44-141-330 4886; Fax: 44-141-330 4063.

Received 8/ 1/95. Accepted 9/27/95.