TFE3, a transcription factor homologous to Microphthalmia, is a potential transcriptional activator of tyrosinase and Tyrpl genes

Abstract

Microphthalmia gene encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor involved in the development of the melanocyte lineage and plays a key role in the transcriptional regulation of the melanogenic enzymes, tyrosinase and Tyrpl. Recently, we have shown that Microphthalmia mediates the melanogenic effects elicited by αMSH that up-regulates the expression of tyrosinase through the activation of the cAMP pathway. Therefore, Microphthalrnia appears as a principal gene in melanocyte development and functioning. Among the transcription factors of the bHLH-Zip family, TFE3 and TFEB show a remarkably elevated homology with Microphthalmia. These observations prompted us to investigate the role of TFE3 and TFEB in the regulation of tyrosinase and Tyrpl gene transcription. We show in this report that overexpression of TFE3 stimulates the tyrosinase and Tyrpl promoter activities, while TFEB acts only on the Tyrpl promoter. TFE3 and TFEB elicit their effects mainly through the binding to Mbox (AGTCATGTGCT) and Ebox motifs (CAT-GTG) of tyrosinase and Tyrpl promoters. In B16 melanoma cells, the high basal expression of TFE3 is down-regulated by forskolin and by αMSH. Interestingly, endogenous TFE3 cannot bind as homodimers to the Mbox, and we did not detect TFE3/Mi heterodimers. According to these data, TFE3 is clearly endowed with the capacity to regulate tyrosinase and Tyrpl gene expression. However, TFE3 binding to the melanogenic gene promoters is hindered, thereby preventing its potential melanogenic action. In specific physiological or pathological conditions, the recovery of its binding function would make TFE3 an important element in melanogenesis regulation.