More On MITF

Abstract

Microphthalmia-associated transcription factor (MITF), a basic-helix-loop-helix (bHLH) and bHLH-leucine zipper transcription factor, is currently an intense focal point in pigment cell biology research. MITF is implicated as the master gene for survival of melanocytes, as well as a key transcription factor regulating the expression of major melanogenic proteins such as tyrosinase and the tyrosinase-related proteins TRP1 and TRP2 (Goding, 2000), via binding to a conserved consensus element, the so-called M-box, in the promoter region of each gene (Yasumoto et al, 1997). Mice bearing null alleles of the MITF gene display complete loss of neural crest-derived melanocytes, deafness and a failure of retinal pigment epithelium differentiation (Goding, 2000). At least two separate mechanisms mediate the diverse biological functions of MITF. First, sustained expression of MITF appears to be modulated through a cAMP-dependent pathway (Bertolotto et al, 1998;Price et al, 1998); and second, MITF function is transiently up-regulated via mitogen-activated protein kinase (MAPK)-dependent phosphorylation of MITF itself (Hemesath et al, 1998). Thus, -melanocyte stimulating hormone (-MSH) and other cAMP-elevating agents transcriptionally up-regulate the expression of MITF through a cAMP-response element (CRE) in the MITF promoter region (Goding, 2000). In contrast, c-kit transiently increases MITF function by a MAPK-mediated phosphorylation of MITF which recruits p300/CBP (CREB-binding protein), a coactivator family that in turn enhances the transcriptional activity of MITF (Hemesath et al, 1998). More recently, MITF was shown to promote survival of pigment cells by up-regulating the expression of the major antiapoptotic protein BCL2 (McGill et al, 2002).