MITF

MITF, or microphthalmia-associated transcription factor, is a transcription factor of the basic helix-loop-helix leucine zipper family. It functions as a master regulator of the development and function of neural crest–derived lineages, most notably melanocytes, the retinal pigment epithelium and mast cells, in vertebrates.

In melanocytes, MITF controls the expression of genes required for pigment production and cell survival, including tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT). Through these targets, MITF influences melanocyte differentiation, proliferation, pigment synthesis, and response to stress.

MITF activity is regulated by multiple signaling pathways, notably MC1R-cAMP/CREB, Wnt/β-catenin, and KIT signaling, which modulate MITF transcription, mRNA stability, and post-translational modifications. The gene produces several protein isoforms via alternative promoter usage, with MITF-M being melanocyte-specific, and other isoforms expressed in retinal pigment epithelium and mast cells.

Clinically, MITF mutations underlie pigmentary disorders such as Waardenburg syndrome type 2 and Tietz syndrome. In cancer, MITF is amplified and overexpressed in a subset of melanomas, where it can act as a lineage survival oncogene. Researchers describe a rheostat model in which higher MITF activity promotes differentiation and cell cycle arrest, whereas lower activity favors proliferation and invasion.