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Activation of the Cyclic AMP Pathway by -Melanotropin Mediates the Response of Human Melanocytes to Ultraviolet B Radiation¹

Department of Dermatology, University of Cincinnati, Cincinnati, Ohio 45267-0592 [S. I., F. P., J. J. N., Z. A-M.]; Shiseido Life Science Research Laboratories, Yokohama, Japan 236 [O. M.]; Huffington Center for Aging Research, Baylor College of Medicine, Houston, Texas 77030 [E. E. M.]; and Shriner's Burns Institute and Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45229 [J. C., G. B.]

A hallmark of sun exposure is increased melanin synthesis by cutaneous melanocytes which protects against photodamage and photocarcinogenesis. Irradiation of human keratinocytes or melanocytes with ultraviolet (UV) rays stimulates the synthesis and release of -melanotropin (-MSH) and adrenocorticotropic hormone (ACTH), which induce cyclic AMP (cAMP) formation and increase the proliferation and melanogenesis of human melanocytes. We report that stimulation of cAMP formation is obligatory for the melanogenic response of cultured normal human melanocytes to UVB radiation. In the absence of cAMP inducers, UVB radiation inhibited, rather than stimulated, melanogenesis. UVB radiation (28 mJ/cm²) arrested melanocytes in the G₁ phase of the cell cycle, and concomitant treatment with 0.1 µM -MSH enhanced their proliferation but did not increase the surviving fraction. Irradiation with UVB, with or without -MSH, caused prolonged expression of p53 and p21(waf-1, cip-1), maintained pRB in a hypophosphorylated state, and reduced the expression of Bcl2. However, -MSH allowed UVB-irradiated melanocytes to enter S phase, suggesting that -MSH acts as a mitogen 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 response of human melanocytes to UV radiation.

¹ Supported in part by RO1-ES06882-01 A1 from the National Institute for Environmental Health Sciences (to Z. A. M.) and K04 AG00594 (to E. E. M.).

² Present address: Ajou University School of Medicine, Department of Dermatology, Suwon, Korea.

³ To whom requests for reprints should be addressed, at Department of Dermatology, University of Cincinnati, P.O. Box 670592, Cincinnati, OH 45267-0592. Phone: (513) 558-6242; Fax: (513) 558-0198.

Received 5/27/97. Accepted 10/24/97.

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