Melanocyte Differentiation Marker gp75, the Brown Locus Protein, Can Be Regulated Independently of Tyrosinase and Pigmentation

Human melanoma arises from epidermal melanocytes and displays remarkable phenotypic heterogeneity. This heterogeneity in part reflects the ability of melanoma cells to undergo differentiation along a pathway parallel to differentiation of normal melanocytes. Tyrosinase, encoded by the albino (c), and the tyrosinase-related protein-1 or gp75, encoded by the brown (b) locus, are two of the best-characterized markers for melanocyte differentiation. Both molecules are glycoproteins expressed in melanosomes, the site of pigment synthesis. We studied the regulation of these proteins in human melanoma cells induced by the polar-planar compound hexamethylene bisacetamide (HMBA). In well-differentiated melanoma cell lines, HMBA induced dendritic morphology and specifically regulated the expression of melanosomal glycoproteins (but not a panel of other molecules expressed by melanoma cells). HMBA specifically down-regulated gp75 expression by rapidly decreasing the steady-state level of gp75 mRNA and gp75 synthesis. HMBA was able to down-regulate gp75 expression even in the presence of cholera toxin, which when added alone induced a two- to threefold increase in gp75 expression. In contrast to uniform down-regulation of gp75 expression, HMBA could either up-regulate or down-regulate tyrosinase expression and pigmentation. Based on the differential regulation of gp75 and tyrosinase, melanoma cells could be classified into two groups. In one group, gp75 expression was coordinately regulated with tyrosinase activity and pigmentation. In the other group, gp75 expression and tyroslnase activity and pigmentation were dissociated (with pigmentation coupling to tyrosinase activity, not to gp75 expression). These results show that in mature melanocytlc cells, regulation of gp75 expression follows a pattern that can be independent of regulation of tyrosinase and pigmentation