Another Mechanism for p53-Mediated Protection

Abstract

Ultraviolet (UV) radiation of the skin stimulates production of melanin, which absorbs UV and free radicals and helps protect the skin from UV-induced DNA damage and skin cancers. This process of tanning depends on activation of the melanocortin-1 receptor by α-melanocyte-stimulating hormone, a product of the pro-opiomelanocortin ( POMC ) gene. Noting that mice lacking the tumor suppressor p53 are extremely susceptible to UV-induced skin cancers, Cui et al . investigated the role of p53 in tanning. After determining that the POMC promoter contains a p53 consensus element, the authors exposed primary human keratinocytes and mouse PAM212 keratinocytes to UV and saw an increase in POMC mRNA and protein, with a peak increase in p53 protein preceding the POMC peak. p53 overexpression in PAM212 cells increased POMC mRNA and protein, whereas a dominant-negative p53 allele inhibited the UV-dependent increase in POMC. Mice lacking p53 failed to show a UV-dependent increase in POMC mRNA or protein, and their ears and tails failed to tan (although basal expression of POMC persisted and fur pigmentation resembled that of wild-type mice). UV stimulated the expression of gene reporters containing the POMC p53-binding site, an effect blocked by site-specific mutation. Electrophoretic mobility shift assay indicated that UV stimulated p53 binding to keratinocyte DNA, and chromatin immunoprecipitation showed that UV stimulated p53 binding to the POMC promoter. The topoisomerase inhibitor etoposide also stimulated p53 and POMC expression, and topical 5-fluorouracil, which is known to induce hyperpigmentation, failed to do so in the skin of mice lacking p53. Thus, the authors propose that p53 acts as a UV sensor to mediate the protective tanning response through transcriptional activation of POMC . Oren and Bartek discuss implications of the research in a Preview. R. Cui, H. R. Widlund, E. Feige, J. Y. Lin, D. L. Wilensky, V. E. Igras, J. D'Orazio, C. Y. Fung, C. F. Schanbacher, S. R. Granter, D. E. Fisher, Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 128 , 853-864 (2007). [Online Journal] M. Oren, J. Bartek, The sunny side of p53. Cell 128 , 826-828 (2007). [Online Journal]