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Molecular and Cellular Biology, December 2006, p. 8914-8927, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.02299-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Microphthalmia-Associated Transcription Factor Mitf Interacts with ß-Catenin To Determine Target Gene Expression{triangledown}

Alexander Schepsky,1 Katja Bruser,2 Gunnar J. Gunnarsson,1 Jane Goodall,3 Jón H. Hallsson,1 Colin R. Goding,3 Eirikur Steingrimsson,1* and Andreas Hecht2

Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavík, Iceland,1 Institute for Molecular Medicine and Cell Science, University of Freiburg, Freiburg, Germany,2 Signal Transduction Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey, United Kingdom3

Received 1 December 2005/ Returned for modification 22 December 2005/ Accepted 9 September 2006

Commitment to the melanocyte lineage is characterized by the onset of expression of the microphthalmia-associated transcription factor (Mitf). This transcription factor plays a fundamental role in melanocyte development and maintenance and seems to be crucial for the survival of malignant melanocytes. Furthermore, Mitf has been shown to be involved in cell cycle regulation and to play important functions in self-renewal and maintenance of melanocyte stem cells. Although little is known about how Mitf regulates these various processes, one possibility is that Mitf interacts with other regulators. Here we show that Mitf can interact directly with ß-catenin, the key mediator of the canonical Wnt signaling pathway. The Wnt signaling pathway plays a critical role in melanocyte development and is intimately involved in triggering melanocyte stem cell proliferation. Significantly, constitutive activation of this pathway is a feature of a number of cancers including malignant melanoma. Here we show that Mitf can redirect ß-catenin transcriptional activity away from canonical Wnt signaling-regulated genes toward Mitf-specific target promoters to activate transcription. Thus, by a feedback mechanism, Mitf can diversify the output of canonical Wnt signaling to enhance the repertoire of genes regulated by ß-catenin. Our results reveal a novel mechanism by which Wnt signaling and ß-catenin activate gene expression, with significant implications for our understanding of both melanocyte development and melanoma.

* Corresponding author. Mailing address: Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland. Phone: 354 525 4270. Fax: 354 525 4886. E-mail: eirikurs{at}hi.is.

{triangledown} Published ahead of print on 25 September 2006.

Molecular and Cellular Biology, December 2006, p. 8914-8927, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.02299-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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