Melanocyte-specific microphthalmia-associated transcription factor isoform activates its own gene promoter through physical interaction with lymphoid-enhancing factor 1.
Waardenburg syndrome type 2 (WS2) is associated with heterozygous mutations in the gene encoding microphthalmia-associated transcription factor (MITF) and characterized by deafness and hypopigmentation due to lack of melanocytes in the inner ear and skin. Melanocyte-specific MITF isoform (MITF-M) is essential for melanocyte differentiation and is transcriptionally induced by Wnt ... signaling that is mediated by beta-catenin and LEF-1. Here we show that MITF-M transactivates its own promoter (M promoter) by interacting with LEF-1, as judged by transient expression assays and in vitro protein-protein binding assays, whereas no transactivation of the M promoter was detected with MITF-M alone or with the combination of MITF-M and dominant-negative LEF1 that lacks the beta-catenin-binding domain. This synergy depends on the three LEF-1-binding sites that are clustered in the proximal M promoter. Importantly, MITF-M recruited on the M promoter could function as a non-DNA-binding cofactor for LEF-1. Thus, MITF-M may function as a self-regulator of its own expression to maintain a threshold level of MITF-M that is required for melanocyte development. We suggest that MITF-M haploinsufficiency may impair the dosage-sensitive role of MITF-M or the correct assembly of multiple transcription factors, involving MITF-M, on the M promoter, which could account for dominant inheritance of WS2.
Mesh Terms:
Animals, Binding Sites, COS Cells, Cell Nucleus, DNA-Binding Proteins, Dose-Response Relationship, Drug, Genes, Dominant, HeLa Cells, Humans, Luciferases, Lymphoid Enhancer-Binding Factor 1, Melanocytes, Microphthalmia-Associated Transcription Factor, Models, Genetic, Mutation, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Signal Transduction, Transcription Factors, Transcriptional Activation, Transfection
Animals, Binding Sites, COS Cells, Cell Nucleus, DNA-Binding Proteins, Dose-Response Relationship, Drug, Genes, Dominant, HeLa Cells, Humans, Luciferases, Lymphoid Enhancer-Binding Factor 1, Melanocytes, Microphthalmia-Associated Transcription Factor, Models, Genetic, Mutation, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Signal Transduction, Transcription Factors, Transcriptional Activation, Transfection
J. Biol. Chem.
Date: Aug. 09, 2002
PubMed ID: 12048204
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