The Identification and Functional Characterization of a Novel Mast Cell Isoform of the Microphthalmia-associated Transcription Factor

The microphthalmia-associated transcription factor (Mitf) is critical for mast cell development based on the severe mast cell deficiency seen in Mitf mutant mice. Mitf also is important for the development of melanocytes, osteoclasts, and retinal pigment epithelium. The lineage-restricted phenotypes...

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Veröffentlicht in:The Journal of biological chemistry 2002-08, Vol.277 (33), p.30244-30252
Hauptverfasser: Takemoto, Clifford M., Yoon, Yo-Jin, Fisher, David E.
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container_issue 33
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container_title The Journal of biological chemistry
container_volume 277
creator Takemoto, Clifford M.
Yoon, Yo-Jin
Fisher, David E.
description The microphthalmia-associated transcription factor (Mitf) is critical for mast cell development based on the severe mast cell deficiency seen in Mitf mutant mice. Mitf also is important for the development of melanocytes, osteoclasts, and retinal pigment epithelium. The lineage-restricted phenotypes of Mitfmutations correlate with tissue-restricted expression of Mitf, a feature due in part to the presence of several distinct Mitf isoforms. We report the identification and characterization of a novel mast cell isoform, Mitf-mc. This isoform arises from alternative splicing of a novel 5′-exon onto the common body of the gene and is predicted to encode a unique 43-amino acid sequence at its amino terminus. It is specifically expressed in mast cells. The mast cell isoform functions differently from the melanocyte isoform in its ability to activate cell type-specific Mitf gene targets. Mitf-mc functions only on a mast cell target promoter and fails to activate a melanocyte target promoter despite binding to its E-box element. Moreover, Mitf-mc heterodimerizes with a closely related transcription factor, Tfe3, and dominantly inhibits the ability of Tfe3 to transactivate a melanocyte-specific promoter. These studies identify a new isoform of Mitf with tissue-specific features that may underlie key aspects of the mast cell phenotype of Mitf mutations.
doi_str_mv 10.1074/jbc.M201441200
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subjects Amino Acid Sequence
Animals
Base Sequence
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Binding Sites
Cell Line
DNA
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Mast Cells - metabolism
Mice
Microphthalmia-Associated Transcription Factor
Molecular Sequence Data
Monophenol Monooxygenase - genetics
Promoter Regions, Genetic
Protein Isoforms - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors - antagonists & inhibitors
Transcription Factors - metabolism
Transcriptional Activation
title The Identification and Functional Characterization of a Novel Mast Cell Isoform of the Microphthalmia-associated Transcription Factor
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