New regulators of melanin biosynthesis and the autodestruction of melanoma cells

Abstract

The hues of mammalian skin and hair vary from white to jet black. Silvers has recently catalogued over 130 different coat colour mutations at more than 50 genetic loci in the house mouse (Mus musculus), a useful model for study¹. Some of these loci govern differentiation of melanocytes and their migration from the neural crest region during embryogenesis². Others, however, involve expression of genes for melanin synthesis within the pigment cell, such as c-locus mutations, where animals are phenotypically albino, c-locus albinism is presumably due to a deficiency of active tyrosinase, the enzyme catalysing the initial steps in the melanin synthetic pathway. It has generally been assumed that the only regulated steps in this pathway are those governed by tyrosinase, since in vitro, melanin is spontaneously formed from dopa quinone (Fig. 1). However, Logan and Weatherhead have provided evidence for post-tyrosinase inhibition of melanogenesis by melatonin in hair follicles of Siberian hamsters⁵, as do our studies with various mutants of Cloudman mouse melanoma cells, suggesting the involvement of a second regulatory site. We describe here three new factors which control melanin synthesis that we have partially purified from Cloudman cells: (1) dopachrome conversion factor (DCF), which accelerates the conversion of dopachrome to 5,6-dihydroxyindole (see ref. 6 for detailed description); (2) 5,6-dihydroxindole conversion factor, which catalyses the conversion of 5,6-dihydroxyindole to melanin and is active only when cells are exposed to melanotropin (MSH), and (3) 5,6-dihydroxyindole blocking factor, which restricts melanogenesis at 5,6-dihydroxyindole. This third factor appears to protect cells from the cytotoxic effects of melanin precursors, and it is removed when the cells are exposed to MSH. Discovery of the factors indicates that regulation of the melanin biosynthetic pathway is more complex than previously supposed.