Activation of the tyrosinase gene promoter by neurofibromin

Neurofibromatosis type 1 (NF1) is a hereditary cancer syndrome, characterized by café-au-lait skin spots and multiple neurofibromas. A gene linked to NF1 encodes neurofibromin, an established function of which is to stimulate intrinsic GTPase activity of ras protein. By transiently coexpressing a neurofibromin cDNA in a melanoma cell line, we show that neurofibromin increases the expression of a reporter gene under the control of the tyrosinase gene promoter. Tyrosinase is a rate-limiting enzyme in melanin biosynthesis and is expressed only in melanin-producing cells. Functional analysis of neurofibromin cDNAs suggests that the domain related to a GTPase-activating protein is mainly responsible for this induction. These results suggest that neurofibromin functions as a regulator of melanogenesis, a process specific to the melanocytes derived from the neural crest.