{beta}-Catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor

doi:10.1083/jcb.200202049

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 transcriptionfactor (MITF) is a lineage-determination factor, which modulatesmelanocyte differentiation and pigmentation. MITF was recentlyshown to reside downstream of the canonical Wnt pathway duringmelanocyte differentiation from pluripotent neural crest cellsin zebrafish as well as in mammalian melanocyte lineage cells.Although expression of many melanocytic/pigmentation markersis lost in human melanoma, MITF expression remains intact, evenin unpigmented tumors, suggesting a role for MITF beyond itsrole in differentiation. A significant fraction of primary humanmelanomas exhibit deregulation (via aberrant nuclear accumulation)of ß-catenin, leading us to examine its role in melanomagrowth and survival. Here, we show that ß-cateninis a potent mediator of growth for melanoma cells in a mannerdependent on its downstream target MITF. Moreover, suppressionof melanoma clonogenic growth by disruption of ß-catenin–T-celltranscription factor/LEF is rescued by constitutive MITF. Thisrescue occurs largely through a prosurvival mechanism. Thus,ß-catenin regulation of MITF expression representsa tissue-restricted pathway that significantly influences thegrowth and survival behavior of this notoriously treatment-resistantneoplasm.

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

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