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A p53-independent Pathway for Induction of p21^waf1cip1 and Concomitant G₁ Arrest in UV-irradiated Human Skin Fibroblasts¹

Centre de Recherche Guy Bernier, Hôpital Maisonneuve-Rosemont, 5415 boulevard de l'Assomption, Montreal, Quebec, Canada HIT 2M4

Largely on the basis of studies using the potent clastogen ionizing radiation, it has been widely assumed that up-regulation of the cyclin-dependent kinase inhibitor p21^waf1cip1 in cultured cells exposed to DNA-damaging agents is contingent upon the presence of functional p53 tumor suppressor protein. Nevertheless, we demonstrate here that the model mutagen 254-nm UV light induces p21^waf1cip1 protein and concomitant G₁ arrest in normal human skin fibroblasts, as well as in p53-deficient fibroblasts derived from cancer-prone Li-Fraumeni syndrome patients. However, as expected, following exposure to ionizing radiation, elevated p21^waf1cip1 protein levels and G₁ arrest were observed only in normal fibroblasts. These data provide a prominent and clinically relevant example in which p21^waf1cip1-mediated growth arrest occurs independently of p53 in human cells treated with a model DNA-damaging agent.

¹ This work was supported by grants from The National Cancer Institute of Canada and The Cancer Research Society, Inc. R. F. holds a postdoctoral fellowship from The Cancer Research Society, Inc. E. A. D. is a scholar of The Medical Research Council of Canada.

² To whom requests for reprints should be addressed. Phone: (514) 252-3400, ext. 4665; Fax: (514) 252-3430; E-mail: drobetse@ere.umontreal.ca.

Received 6/ 2/97. Accepted 7/ 2/97.

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