Microphthalmia-associated transcription factor (MITF): multiplicity in structure, function, and regulation.
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.
Shibahara
S
S
Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Miyagi, Japan. shibahar@mail.cc.tohoku.ac.jp
Takeda
K
K
Yasumoto
K
K
Udono
T
T
Watanabe
K
K
Saito
H
H
Takahashi
K
K
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology; D015398:Signal Transduction; D013991:Tietze's Syndrome / Q000235:genetics; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins