Melanocyte-specific microphthalmia-associated transcription factor isoform activates its own gene promoter through physical interaction with lymphoid-enhancing factor 1.

Hideo Saito, Ken Ichi Yasumoto, Kazuhisa Takeda, Kazuhiro Takahashi, Atsushi Fukuzaki, Seiichi Orikasa, Shigeki Shibahara

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74 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)28787-28794
Number of pages8
JournalThe Journal of biological chemistry
Volume277
Issue number32
DOIs
Publication statusPublished - 2002 Aug 9

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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