The role of excessive sun exposure in the etiology of skin cancers is well recognized. Human melanocytes respond directly to UV irradiation with increased melanin formation and inhibition of proliferation. It has been documented that the mutagenic effects of UV light, particularly in the form of UVB, result from DNA damage, mostly in the form of cyclobutane pyrimidine dimers, and pyrimidine (6,4) pyrimidone photoproducts. Previous studies on murine melanoma cells have implicated alpha-melanocyte stimulating hormone (alpha-MSH) as the mediator of the UV-induced effects on proliferation and melanogenesis. The role of alpha-MSH as a physiologic regulator of human melanocytes is controversial. So far, there has been no convincing evidence that alpha-MSH directly affects human melanocytes in a significant manner. We have just been able to demonstrate that human melanocytes respond to alpha-MSH with a marked increase in proliferation and melanogenesis. This response required establishing melanocyte cultures in the absence of cholera toxin, and maintaining them in the absence of cAMP inducers for the duration of treatment with alpha-MSH. We have also found that UV-irradiated melanocytes respond to alpha-MSH with augmentation of the UV-induced melanogenesis and enhancement of proliferation. The ability of alpha-MSH to override the inhibitory effect of UV light on the proliferation of human melanocytes might result in the persistence of the UV-induced DNA damage, which potentially can lead to carcinogenesis. We propose that alpha-MSH might act as a transducer for the effects of UV light on human melanocytes. Therefore, we will investigate the mechanisms by which UV light and alpha-MSH interact to affect human melanocyte proliferation, melanogenesis, genotoxicity and gene expression. We will compare the amount of cyclobutane pyrimidine dimers and pyrimidine (6,4) pyrimidone photoproducts in melanocytes irradiated with UV light, or irradiated with UV light then treated with alpha-MSH. We will also investigate the regulation of expression of the melanocortin receptors by alpha-MSH and UV light, and the signal transduction pathways induced by UV irradiation and alpha-MSH. Since stimulation of melanogenesis by sun exposure is directly related to the constitutive pigmentation of human skin, melanocyte strains with different constitutive melanin contents, derived from individuals with different skin types, will be used in all the studies proposed. Our results, and the reports that alpha-MSH is synthesized in the skin and by human melanoma cells suggest a role for alpha-MSH in photocarcinogenesis, as an autocrine/paracrine regulator of melanoma tumor formation.
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