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

Abstract

Wnt ligands have pleiotropic and context-specific roles in embryogenesis and adult tissues. Among other effects, certain Wnts stabilize the B-catenin protein, leading to the ability of B-catenin to activate T-cell factor (TCF)-mediated transcription. Mutations resulting in constitutive B-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/B-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 B-catenin dysregulation. When ectopically expressed, the silencing mediator for retinoid and thyroid receptors/ histone deacetylase 1-associated repressor protein (SHARP) protein potently enhanced B-catenin/TCF transcription of a model reporter gene and cellular target genes. Inhibition of endogenous SHARP function via RNA inhibitory (RNAi) approaches antagonized B-catenin/TCF-mediated activation of target genes. The effect of SHARP on B-catenin/TCF-regulated genes was mediated via a functional interaction between SHARP and TCF. B-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 B-catenin dysregulation. [Cancer Res 2007;67(2):482-91]

An autonomous metabolic role for Spen

“…Spen promotes Wingless (Wg) signaling in flies and the orthologous Wnt signaling pathway in mammals [20, 21], and suppresses Notch signaling in flies and mammals [22–26]. Spen contains three RNA recognition motifs (RRMs) near its N terminus and, near the C terminus, the archetype Spen paralog and ortholog C-terminal (SPOC) domain [27].…”

Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression

“…The function of PTOV1 as a Notch co-repressor could also differ from that of SKIP [60], since we show here that PTOV1 interacts with the Notch repressor complex, but not with Notch1. Similarly, SHARP, another Notch co-repressor, also interacts with the same inhibitors as PTOV1 [51,61,62], but shows different expression patterns in human tumors [6,61]. …”

Wnt signaling and neural stem cells: caught in the Wnt web

“…Importantly, synergistic interactions occur also with homeodomain family proteins such as Alx4 on the NCAM promoter (Boras and Hamel 2002), Pitx2 on LEF1 (Vadlamudi et al 2005) and Cdx1 on its own promoter (Beland et al 2004). Another tempting Tcf/ LEF-interacting partner that can significantly enhance transcriptional activation of target genes (Feng et al 2007) is the Drosophila split ends (spen) homologue, known as MINT (Msx2-interacting nuclear targeting protein) in mouse or SHARP (SMRT/Hdac1-associated receptor protein) in human. The functional interaction between SHARP and Tcf/LEF was shown to be independent on β-catenin.…”