Ultraviolet radiation down-regulates expression of the cell-cycle inhibitor p21WAF1/CIP1 in human cancer cells independently of p53

Author： Wang J. A. Fan S. Yuan R. Q. X. Y. Meng Q. Goldberg I. D. Rosen E. M.

Publisher： Informa Healthcare

ISSN： 1362-3095

Source： International Journal of Radiation Biology, Vol.75, Iss.3, 1999-03, pp. : 301-316

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Abstract

Purpose : To investigate the regulation of G1 cyclin-dependent kinase inhibitor p21WAF1/CIP1 by ultraviolet (UV) radiation in human carcinoma cells. Materials and methods : Human cancer cell lines were irradiated with UV-C (254nm) radiation, and their responses were characterized by Western blotting, Northern blotting, semi-quantitative RT-PCR analysis, trypan blue staining and flow cytometric cell cycle analysis. Results : At 24 h after UV irradiation, p21 expression was downregulated in various cancer cell types (breast, prostrate, cervix, colon, glioma, squamous cancers), independently of their p53 genetic and functional status. UV-mediated down-regulation of p21 was dose- and time-dependent, was observed at the protein and mRNA levels, and did not correlate with cytotoxicity. Reduction of p21 protein levels required about 4 and 1 h, respectively, in MCF-7 and MDA-MB-231 breast cancer cells; some of the UV-induced decreases in p21 levels in these cell lines was due to enhanced proteasomal degradation. Despite decreased p21 levels, UV-irradiated breast cancer cells with wildtype p53 (MCF-7) retained the capacity for G1 cell-cycle arrest, whereas UV-treated cells with mutant p53 (MDA-MB-231) accumulated in S phase, suggesting a p53-dependent G1 checkpoint in MCF-7. UV treatment caused other alterations in cellcycle regulatory, DNA repair and tumour suppressor genes, as described in this report. Conclusions : In contrast to X-rays, UV causes down-regulation of the cell-cycle inhibitor p21 in tumour cells. It is postulated that this may be an adaptation to promote the growth and survival of transformed cells.