A basic domain-derived tripeptide inhibits MITF activity by reducing its binding to promoter of target genes.

Abstract The keratinocytes in ultraviolet (UV)-irradiated skin produce and secrete α-melanocyte-stimulating hormone (α-MSH). α-MSH upregulates the expression of microphthalmia-associated transcription factor (MITF) in melanocytes via the cyclic adenosine monophosphate/protein kinase A/cAMP response element-binding protein (cAMP/PKA/CREB) signaling pathway. Thereafter, MITF induces the expression of melanogenic genes, including the tyrosinase, tyrosinase related protein-1 (TYRP-1), and tyrosinase related protein-2 (TYRP-2) genes, which leads to the synthesis and accumulation of melanin. In this study, we examined whether MITF basic region-derived tripeptides can bind to DNA-binding domain of MITF and inhibit MITF-induced melanogenesis through the inhibition of MITF-DNA binding. MITF-KGR, a representative MITF-derived tripeptide, suppressed the transcriptional activity of MITF by disrupting its binding to the promoter region of the target genes, which resulted in the inhibition of skin epidermis thickness and melanin synthesis in vivo and in vitro. Our results indicate that MITF-KGR exerts an inhibitory effect on melanogenesis by targeting MITF.