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
J. Biol. Chem.
Date: Aug. 09, 2002
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