Microphthalmia-Associated Transcription Factor (MITF): Multiplicity in Structure, Function, and Regulation

Abstract

Microphthalmia-associated transcription factor (MITF) regulates the differentiation and development of melanocytes and retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the MITF gene cause auditory-pigmentary syndromes. MITF consists of at least five isoforms, MITF-A, MITF-B, MITF-C, MITF-H, and MITF-M, differing at their N-termini and expression patterns. Here we show a remarkable similarity between the N-terminal domain of MITF-A and cytoplasmic retinoic acid-binding proteins. To date, four isoform-specific first exons have been identified in the MITF gene: exons 1A, 1H, 1B, and 1M in the 5' to 3' direction, each of which encodes the unique N-terminus of a given isoform. The 5'-flanking regions of these isoform-specific exons are termed A, H, B, and M promoters, respectively. Among these promoters, the M promoter has received particular attention, because it is functional only in melanocyte-lineage cells and is upregulated by Wnt signaling via the functional LEF-1-binding site. Moreover, the M promoter is upregulated by other transcription factors, PAX3, SOX10, and CREB. The activity and degradation of MITF-M are regulated by extracellular signals via protein phosphorylation, such as c-Kit signaling. Together, multiple signals appear to converge on the M promoter as well as on MITF proteins, leading to the proper regulation of MITF-M in melanocytes and other MITF isoforms in many cell types.

Bone morphogenetic proteins differentially regulate pigmentation in human skin cells

“…These results suggest that the Smad pathway may not play any significant role in BMP-mediated regulation of melanin synthesis. It is also unlikely that a Smad-dependent pathway is directly involved in the upregulation of MITF-M transcripts in MC, because the promoter region of MITF gene does not contain a DNA consensus sequence for Smad binding sites (Shibahara et al, 2001). By contrast, we report here that Smad1/5/8 activation plays a crucial role in melanin transfer to KC under both basal and BMP6 stimulated conditions.…”

The Importance of MITF Signaling Pathway in the Regulation of Proliferation and Invasiveness of Malignant Melanoma

“…MITF-M obsahuje viacero špecifických domén (obr. 1) [5]. V centrálnej časti molekuly proteín MITF obsahuje zásaditú oblasť s motívom helix-slučka-helix-leucínový zips (basic helix-loop-helix-leucine zipper -bHLH LZ), ktorá je zodpovedná za väzbu na DNA a dimerizáciu proteínu.…”

Horizontal gene transfers and cell fusions in microbiology, immunology and oncology (Review)

“…In contrast, a MITF C-terminal product arrived at by cleavage is pro-apoptotic. MITF requires the chromatin remodeling enzymes SWI/SNF (switching, in saccharomyces and sans fille in drosophila) in order to activate melanocyte-specific genes (236)(237)(238)(239). Overexpression of all the above listed receptors in metastatic melanoma cells strongly suggests that these tumor cells have hybridized with macrophages and are driven by an excessive gene load to grow by capturing their ligands MC, MSH and HGF/SF.…”