Transforming growth factor-beta1 decreases melanin synthesis via delayed extracellular signal-regulated kinase activation.
Transforming growth factor-beta1 (TGF-beta1) plays a pivotal role in cell proliferation, differentiation, and apoptosis. In this study, we investigated the effects of TGF-beta1 on melanogenesis using a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Our results show that TGF-beta1 significantly inhibits melanin synthesis in a concentration-dependent manner and that it reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme. We also found that TGF-beta1 reduces microphthalmia-associated transcription factor (MITF) promoter activity and decreased MITF, tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2 protein production. In addition, TGF-beta1 was found to induce a delay in the activation of extracellular signal-regulated kinase (ERK) at 6h, whereas many growth factors activate ERK transiently in minutes. Moreover, the specific ERK pathway inhibitor, PD98059 blocked the hypopigmenting effects induced by TGF-beta1. PD98059 was also found to abrogate the TGF-beta1-mediated down-regulation of MITF, tyrosinase, TRP-1, and TRP-2 production. These results suggest that the ERK pathway may be involved in the melanogenic signaling cascade, and that delayed ERK activation by TGF-beta1 contributes to reduced melanin synthesis via MITF down-regulation.
Kim
Dong-Seok
DS
Department of Dermatology, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, South Korea.
Park
Seo-Hyoung
SH
Park
Kyoung-Chan
KC
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D014442:Monophenol Monooxygenase / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C508961:Tgfb1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014442:Monophenol Monooxygenase