TYROSINASE RELATED PROTEIN-1 AND BROWN OCA

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DESCRIPTION: (Adapted from the applicant's abstract) - TRP-1, a member of the family of melanocyte-specific gene products involved in melanin synthesis, is a scientific enigma. Of the group of molecules, TRP-1 was identified serendipitously by several independent groups attempting to clone tyrosinase, the c-locus protein. This unveiling of TRP-1 resulted because antisera generated against tyrosinase had, unbeknownst at the time, cross-reacted with TRP-1. This illustrates another interesting feature of TRP-1, an intracellular protein: it appears to be extremely immunogenic. Serum antibodies and autoreactive T-cells against TRP-1 have been identified in patients with melanoma. Also, the appearance of TRP-1 antibodies correlates with the expression of vitiligo in an avian model, the Smyth chicken. Of interest are reports of autoantibodies recognizing a glycoprotein of 75 kDA (the m.w. of TRP-1) in patients with vitiligo which may be TRP-1. However, despite the prominence of TRP-1 in scientific/medical research, the role of TRP-1 in melanogenesis has been elusive. The applicants are certain that mutations of TRP-1 result in the synthesis of brown as opposed to black pelage in mice. However, the role of TRP-1 in human hair, as well as skin, pigmentation or how mutations in TRP-1 affect these tissues, has not been elucidated. The applicants propose to analyze the molecular role of TRP-1 in the synthesis of melanin using three avenues of investigation. First they will investigate how TRP-1 regulates the catalytic function of tyrosinase/TRP-1 and/or TRP-2, physically interacts with tyrosinase/TRP-2, and expresses a putative catalytic function(s) using defined melanoma cells and fibroblasts transfected with TRP-1 cDNA and the Matchmaker Two-Hybrid System for analyzing protein interactions. Second, mutational mapping of molecular domains responsible for these functions of TRP-1 will be addressed. Third, melanocytes from patients with tyrosinase-positive OCA expressing mutations affecting TRP-1, and from mice carrying mutant alleles at the brown locus, will be analyzed for defects in melanin synthesis. These studies will elucidate the function of TRP-1, its interaction with other melanocyte-specific gene products, and its role in the pathophysiology of human pigmentary diseases, specifically Brown OCA. These studies will also contribute to our knowledge of melanogenesis and the role of the melanocyte in the skin.