MELANOCYTE DIFFERENTIATION MARKER GP75, THE BROWN LOCUS PROTEIN, CAN BE REGULATED INDEPENDENTLY OF TYROSINASE AND PIGMENTATION

Human melanoma arises from epidermal melanocytes and displays remarkab le phenotypic heterogeneity, This heterogeneity in part reflects the a bility of melanoma cells to undergo differentiation along a pathway pa rallel to differentiation of normal melanocytes, Tyrosinase, encoded b y the albino (c), and the tyrosinase-related protein-1 or gp75, encode d by the brown (b) locus, are two of the best-characterized markers fo r melanocyte differentiation. Both molecules are glycoproteins express ed in melanosomes, the site of pigment synthesis. We studied the regul ation of these proteins in human melanoma cells induced by the polar-p lanar compound hexamethylene bisacetamide (HMBA). In well-differentiat ed melanoma cell lines, HMBA induced dendritic morphology and specific ally regulated the expression of melanosomal glycoproteins (but not a panel of other molecules expressed by melanoma cells), HMBA specifical ly down-regulated gp75 expression by rapidly decreasing the steady-sta te level of gp75 mRNA and gp75 synthesis, HMBA was able to down-regula te gp75 expression even in the presence of cholera toxin, which when a dded alone induced a two- to threefold increase in gp75 expression, In contrast to uniform down-regulation of gp75 expression, HMBA could ei ther up-regulate or down-regulate tyrosinase expression and pigmentati on. Based on the differential regulation of gp75 and tyrosinase, melan oma cells could be classified into two groups, In one group, gp75 expr ession was coordinately regulated with tyrosinase activity and pigment ation, In the other group, gp75 expression and tyrosinase activity and pigmentation were dissociated (with pigmentation coupling to tyrosina se activity, not to gp75 expression), These results show that in matur e melanocytic cells, regulation of gp75 expression follows a pattern t hat can be independent of regulation of tyrosinase and pigmentation.