Transforming growth factor-β1 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 6 h, 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. (C) 2003 Elsevier Ltd. All rights reserved.