Regulation of melanogenesis through phosphatidylinositol 3-kinase-Akt pathway in human G361 melanoma cells.
The involvement of the phosphatidylinositol 3-kinase pathway in the regulation of melanogenesis was examined using human G361 melanoma cells. In the cells 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 treatment 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 negative of phosphatidylinositol 3-kinase, both the melanin content and the expression of tyrosinase increased. In cells infected with the adenovirus vector encoding the constitutively active mutant of the lipid kinase, a decrease in melanin content as well as reduced expression of tyrosinase was observed. In cells expressing the constitutively active mutant of the serine-threonine protein kinase Akt, one of the downstream targets of phosphatidylinositol 3-kinase, the melanin content decreased as in the cells overproducing the constitutively active mutant of phosphatidylinositol 3-kinase. These results indicate that phosphatidylinositol 3-kinase regulates melanogenesis by modulating the expression of tyrosinase, and that activation of Akt is sufficient for suppression of melanin production in G361 melanoma cells.
Oka
M
M
Department of Dermatology, Kobe University School of Medicine, Japan. oka@med.kobe-u.ac.jp
Nagai
H
H
Ando
H
H
Fukunaga
M
M
Matsumura
M
M
Araki
K
K
Ogawa
W
W
Miki
T
T
Sakaue
M
M
Tsukamoto
K
K
Konishi
H
H
Kikkawa
U
U
Ichihashi
M
M
D000730:Androstadienes / Q000494:pharmacology; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008545:Melanoma / Q000209:etiology* / Q000473:pathology; D009154:Mutation; D009183:Mycotoxins / Q000494:pharmacology; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000077191:Wortmannin
D000730:Androstadienes; D008543:Melanins; D009183:Mycotoxins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015682:Retroviridae Proteins, Oncogenic; D000077191:Wortmannin