This project is focused on characterizing parameters important to the growth and differentiation of melanocytes and their significance to the proliferation and metastasis of transformed melanocytes (termed malignant melanoma). Our studies have identified, isolated and characterized several different specific melanogenic enzymes and structural matrix proteins that regulate the quality and quantity of melanin pigment produced within melanocytes. These proteins are encoded within a family of pigmentation-related genes that are specifically expressed by mammalian melanocytes and mutations in a number of these genes have now been shown to be involved in several different human clinical pigmentary diseases. Although expression of these genes is specific to pigment producing tissues, they are independently regulated following stimulation or inhibition of differentiation by various paracrine and autocrine factors, such as ultraviolet light or melanocyte stimulating hormone. The phenotypic and functional properties of the melanins produced by these regulatory catalytic controls differ dramatically, and effects on the functional and photoprotective properties of those melanins are being characterized. We have recently used differential display to identify a subset of novel genes involved in modulating pigmentation in response to another paracrine factor termed the agouti protein and our current research in this area is aimed at characterizing those gene products and the nature of the regulatory mechanisms involved. We have continued to characterize melanoma-specific antigens abnormally expressed by transformed melanocytes which play a role in immune responses to tumor growth. Of great interest is the fact that many of those antigens, including tyrosinase, TRP1, gp100 and MART1, are normally expressed melanosomal specific proteins. Monoclonal antibodies generated in our laboratory to one of those melanocyte membrane antigens, termed B700, specifically cross-react with human melanoma and have proven useful as a highly specific probe for malignant melanoma. Intravenous treatment of tumor-bearing hosts with those monoclonal antibodies provides significant protection against metastatic growth, and B700 constitutes the major immunodominant antigen in a vaccine directed against melanoma tumor growth. Current work in this part of the project is targeted at obtaining sufficient amino acid sequence for B700 to be useful towards the goal of cloning its encoding gene.
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