Regulation of melanogenesis through phosphatidylinositol 3-kinase-Akt pathway in human G361 melanoma cells

The involvement of the phosphatidylinositol 3-kinase pathway in the regulat ion of melanogenesis was examined using human G361 melanoma cells. In the c ells treated with wortmannin, a potent inhibitor of phosphatidylinositol 3- kinase, the melanin content increased concomitant with the elevated protein level of tyrosinase, a key enzyme in melanogenesis. Northern blot analysis revealed that the mRNA level of tyrosinase increased transiently on treatm ent of the cells with the phosphatidylinositol 3-kinase inhibitor. When the cells were infected with the adenovirus vector encoding the mutant adapter subunit of phosphatidylinositol 3-kinase, which acts as a dominant negativ e of phosphatidylinositol 3-kinase, both the melanin content and the expres sion of tyrosinase increased. In cells infected with the adenovirus vector encoding the constitutively active mutant of the lipid kinase, a decrease i n melanin content as well as reduced expression of tyrosinase was observed. In cells expressing the constitutively active mutant of the serine-threoni ne protein kinase Akt, one of the downstream targets of phosphatidylinosito l 3-kinase, the melanin content decreased as in the cells overproducing the constitutively active mutant of phosphatidylinositol 3-kinase. These resul ts indicate that phosphatidylinositol 3-kinase regulates melanogenesis by m odulating the expression of tyrosinase, and that activation of Akt is suffi cient for suppression of melanin production in G361 melanoma cells.