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Department of Otolaryngology—Head and Neck Surgery, Head and Neck Cancer Research Division [W. H. L., D. A. S., J. R., S. A. A., W. K., D. S.], The Johns Hopkins Oncology Center, Department of Medical Oncology [W. H. L., D. S.], and the Department of Surgery [S. A. A.], Johns Hopkins University, Baltimore, Maryland 21205
p16 (CDKN2/MTS1/p16INK4a) is frequently deleted, methylated, or mutated in many malignancies including squamous cell carcinoma of the head and neck (HNSCC). p16ß is an alternative transcript derived from a newly described exon (exon 1ß) located more than 15 kb 5' to exon 1 of p16. Moreover, the p16ß transcript theoretically encodes a protein distinct from p16 derived from a divergent reading frame putatively initiated in exon 1ß. To test the contribution of both of these transcripts in carcinogenesis, full-length cDNA of p16 and p16ß were cloned in separate vector constructs and then transfected into HNSCC cell lines characterized for p16 status (p16[+/+], p16[mut/-], and p16[methylated]). Transfection of either p16 or p16ß resulted in marked growth inhibition in all three HNSCC lines tested, regardless of p16 status. However, p16ß but not p16 inhibited the growth of HeLa cells, a cell line with inactive pRB due to expression of E7 papillomavirus protein. Moreover, transfection of all three HNSCC lines with either p16 or p16ß resulted in a marked increase in cells in G0-G1 consistent with a cell cycle arrest in G1. These data are consistent with the hypothesis that p16 and p16ß are growth-inhibitory genes active in HNSCC and that both act by blocking progression through the G1-S transition of the cell cycle. Furthermore, the suppressive effects of p16ß on HeLa growth suggest that p16ß mediates its effect independently from pRB.
1 Supported by Lung SPORE Grant CA-58184-01 and a Collaborative Research Agreement with Oncor, Inc., Gaithersburg, MD.
2 Contributed equally to this work.
3 To whom requests for reprints should be addressed, at Johns Hopkins University School of Medicine, 818 Ross Research Building, 720 Rutland Ave., Baltimore, MD 21205-2196.
Received 5/16/96. Accepted 7/31/96.
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