Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling

Abstract

Wnt signals regulate differentiation of neural crest cells through the b-catenin associated with a nuclear mediator of the lymphoid-enhancing factor 1 (LEF-1)/ T-cell factors (TCFs) family. Here we show the interaction between the basic helix±loop±helix and leucine-zipper region of microphthalmia-associated transcription factor (MITF) and LEF-1. MITF is essential for melanocyte differentiation and its heterozygous mutations cause auditory±pigmentary syndromes. Functional cooperation of MITF with LEF-1 results in synergistic transactivation of the dopachrome tautomerase (DCT) gene promoter, an early melanoblast marker. This activation depends on the separate cis-acting elements, which are also responsible for the induction of the DCT promoter by lithium chloride that mimics Wnt signaling. b-catenin is required for ef®cient transactivation, but dispensable for the interaction between MITF and LEF-1. The interaction with MITF is unique to LEF-1 and not detectable with TCF-1. LEF-1 also cooperates with the MITF-related proteins, such as TFE3, to transactivate the DCT promoter. This study therefore suggests that the MITF/TFE3 family is a new class of nuclear modulators for LEF-1, which may ensure ef®cient propagation of Wnt signals in many types of cells.

Malignant melanoma: genetics and therapeutics in the genomic era

“…Additional studies identified similar biochemical relationships between Wnt effectors (␤-catenin, TCF/LEF) and Mitf expression in murine and human melanocytes and melanoma cells (Takeda et al 2000b;Widlund et al 2002). Interactions have also been observed between LEF-1 and MITF, suggesting that MITF may function as an alternative coactivator of certain Wnt-signaling targets (independent of ␤-catenin) (Yasumoto et al 2002).…”

“…Using candidate approaches, multiple pigmentation-associated factors have been thus recognized, although it is noteworthy that factors other than MITF are undoubtedly important in their regulation as well, because the endogenous genes are not always predictably up-or down-regulated by modulation of Mitf expression alone (Gaggioli et al 2003). Other transcription factors of importance in the regulation of potential Mitf targets include CREB/ATF1, SOX10 (Jiao et al 2004;Ludwig et al 2004), Pax3 (as a negative regulator and potential media-tor of melanocyte stem cell maintenance) (Lang et al 2005), OTX2 in retinal pigment epithelium (MartinezMorales et al 2003), CBP and MAZR (in mast cells) (Ogihara et al 1999;Morii et al 2002), Pu.1 in osteoclast target genes Luchin et al 2001;Cassady et al 2003;So et al 2003;Partington et al 2004), Wnt/ LEF (Yasumoto et al 2002), and probably others as well.…”

Transcriptional Activation of Mouse Mast Cell Protease-7 by Activin and Transforming Growth Factor-β Is Inhibited by Microphthalmia-associated Transcription Factor

“…Smad3-mediated transcriptional activation paralleled the protein level, suggesting that Smad regulation by MITF is achieved through modulation of the Smad protein level. MITF could form a complex with LEF-1, a signal mediator of the Wnt pathway, but the association was not sufficient for efficient transactivation of genes activated by the Wnt pathway (53). In addition, both Max, another member of the bHLHLZ family, and TFE3 bound to the MH1 region of Smad3 in vitro, but Max and TFE3 had opposite effects on Smad3-mediated transcriptional activation (49,54).…”

Regulation of MITF stability by the USP13 deubiquitinase

“…For example, α-melanocyte-stimulating hormone strongly increases MITF expression through a cyclic AMP and CREB/ATF1-mediated pathway [6][7][8] . In addition, through its melanocyte-specific promoter (M-MITF), the expression of MITF is regulated by paired box gene 3 (PAX3), SRY (sex-determining region Y)-box 10 (SOX10), lymphoid enhancerbinding factor 1 (LEF1), and one cut domain 2 (ONECUT-2) [9][10][11][12] In Clear Cell Sarcoma the EWS-ATF1 fusion oncoprotein occupies the MITF promoter, constitutively replaces the cAMP-driven activity of CREB/ATF1soasto mimicking melanocyte-stimulating hormone signalling to induce expression of MITF 13 . In this kind of tumour MITF appears to have an oncogenic role as well 13 .…”