This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feng, Y. Articles by Fearon, E. R. Search for Related Content PubMed PubMed Citation Articles by Feng, Y. Articles by Fearon, E. R.

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]

This article has been cited by other articles:

				C. Niu, J. Zhang, P. Breslin, M. Onciu, Z. Ma, and S. W. Morris c-Myc is a target of RNA-binding motif protein 15 in the regulation of adult hematopoietic stem cell and megakaryocyte development Blood, September 3, 2009; 114(10): 2087 - 2096. [Abstract] [Full Text] [PDF]