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Published 16 September 2002. doi:10.1083/jcb.200202049
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© The Rockefeller University Press, 0021-9525/2002/9/1079 $5.00
The Journal of Cell Biology, Volume 158, Number 6, September 16, 2002 1079-1087

Article

ß-Catenin–induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor



Hans R. Widlund1, Martin A. Horstmann1, E. Roydon Price1, Junqing Cui1, Stephen L. Lessnick1,2, Min Wu1, Xi He2 and David E. Fisher1,2

1 Department of Pediatric Oncology, Dana-Farber Cancer Institute
2 Children's Hospital, Harvard Medical School, Boston, MA 02115

Address correspondence to David E. Fisher, Dana-Farber Cancer Institute, Pediatric Oncology, Dana 630, 44 Binney St., Boston, MA 02115. Tel.: (617) 632-4916. Fax: (617) 632-2085. E-mail: David_Fisher{at}dfci.harvard.edu

The transcription factor Microphthalmia-associated transcription factor (MITF) is a lineage-determination factor, which modulates melanocyte differentiation and pigmentation. MITF was recently shown to reside downstream of the canonical Wnt pathway during melanocyte differentiation from pluripotent neural crest cells in zebrafish as well as in mammalian melanocyte lineage cells. Although expression of many melanocytic/pigmentation markers is lost in human melanoma, MITF expression remains intact, even in unpigmented tumors, suggesting a role for MITF beyond its role in differentiation. A significant fraction of primary human melanomas exhibit deregulation (via aberrant nuclear accumulation) of ß-catenin, leading us to examine its role in melanoma growth and survival. Here, we show that ß-catenin is a potent mediator of growth for melanoma cells in a manner dependent on its downstream target MITF. Moreover, suppression of melanoma clonogenic growth by disruption of ß-catenin–T-cell transcription factor/LEF is rescued by constitutive MITF. This rescue occurs largely through a prosurvival mechanism. Thus, ß-catenin regulation of MITF expression represents a tissue-restricted pathway that significantly influences the growth and survival behavior of this notoriously treatment-resistant neoplasm.

Key Words: Wnt-signaling; ß-catenin; MITF; survival; melanoma


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