ACTIVATION OF THE CYCLIC-AMP PATHWAY BY ALPHA-MELANOTROPIN MEDIATES THE RESPONSE OF HUMAN MELANOCYTES TO ULTRAVIOLET-B RADIATION

A hallmark of sun exposure is increased melanin synthesis by cutaneous melanocytes which protects against photodamage and photocarcinogenesi s, Irradiation of human keratinocytes or melanocytes with ultraviolet (UV) rays stimulates the synthesis and release of alpha-melanotropin ( alpha-MSH) and adrenocorticotropic hormone (ACTH), which induce cyclic AMP (cAMP) formation and increase the proliferation and melanogenesis of human melanocytes. Re report that stimulation of cAMP formation is obligatory for the melanogenic response of cultured normal human mela nocytes to UVB radiation, In the absence of cAMP inducers, UVB radiati on inhibited, rather than stimulated, melanogenesis. UVB radiation (28 mJ/cm(2)) arrested melanocytes in the G(1) phase of the cell cycle, a nd concomitant treatment with 0.1 mu M alpha-MSH enhanced their prolif eration but did not increase the surviving fraction, Irradiation with UVB, with or without alpha-MSH, caused prolonged expression of p53 and p21(waf-1, cip-l), maintained pRB in a hypophosphorylated state, and reduced the expression of Bcl2, However, (U-MSH allowed UVB-irradiated melanocytes to enter S phase, suggesting that alpha-MSH acts as a mit ogen rather than a survival factor, and that overexpression of p53 is mainly a signal for cell death, Our results underscore the importance of the cAMP pathway and its physiological inducers in mediating the re sponse of human melanocytes to UV radiation.