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Drosophila split ends Homologue SHARP Functions as a Positive Regulator of Wnt/ß-Catenin/T-Cell Factor Signaling in Neoplastic Transformation

Departments of ¹ Internal Medicine, ² Pathology, ³ Molecular, Cellular, and Developmental Biology, and ⁴ Human Genetics and ⁵ The Cancer Center, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Eric R. Fearon, Division of Molecular Medicine and Genetics, University of Michigan School of Medicine, 109 Zina Pitcher, 1504 BSRB, Ann Arbor, MI 48109-2200. Phone: 734-764-1549; Fax: 734-647-7950; E-mail: fearon{at}umich.edu.

Wnt ligands have pleiotropic and context-specific roles in embryogenesis and adult tissues. Among other effects, certain Wnts stabilize the ß-catenin protein, leading to the ability of ß-catenin to activate T-cell factor (TCF)-mediated transcription. Mutations resulting in constitutive ß-catenin stabilization underlie development of several human cancers. Genetic studies in Drosophila highlighted the split ends (spen) gene as a positive regulator of Wnt-dependent signaling. We have assessed the role of SHARP, a human homologue of spen, in Wnt/ß-catenin/TCF function in mammalian cells. We found that SHARP gene and protein expression is elevated in human colon and ovarian endometrioid adenocarcinomas and mouse colon adenomas and carcinomas carrying gene defects leading to ß-catenin dysregulation. When ectopically expressed, the silencing mediator for retinoid and thyroid receptors/histone deacetylase 1-associated repressor protein (SHARP) protein potently enhanced ß-catenin/TCF transcription of a model reporter gene and cellular target genes. Inhibition of endogenous SHARP function via RNA inhibitory (RNAi) approaches antagonized ß-catenin/TCF-mediated activation of target genes. The effect of SHARP on ß-catenin/TCF-regulated genes was mediated via a functional interaction between SHARP and TCF. ß-Catenin–dependent neoplastic transformation of RK3E cells was enhanced by ectopic expression of SHARP, and RNAi-mediated inhibition of endogenous SHARP in colon cancer cells inhibited their transformed growth. In toto, our findings implicate SHARP as an important positive regulator of Wnt signaling in cancers with ß-catenin dysregulation. [Cancer Res 2007;67(2):482–91]