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Vol. 17, Issue 6, 2572-2580, June 2006

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Engrailed-1 Negatively Regulates -Catenin Transcriptional Activity by Destabilizing -Catenin via a Glycogen Synthase Kinase-3–independent Pathway

Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Submitted January 18, 2006; Revised February 27, 2006; Accepted March 16, 2006
Monitoring Editor: Carl-Henrik Heldin

The Wnt signaling pathway plays a major role in development, and upon deregulation it is implicated in neoplasia. The hallmark of the canonical Wnt signal is the protection of -catenin from ubiquitination and proteasomal degradation induced by glycogen synthase kinase (GSK)-3 inhibition. The stabilized -catenin translocates to the nucleus where it binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the expression of Wnt target genes. In the absence of Wnt signal, TCF/LEF bind to Groucho (Gro)/TLE corepressors and repress Wnt target genes. Gro/TLE bind also to Engrailed (En) transcription factors mediating En-repressive activity on En target genes. Here, we present data suggesting that En-1 serves also as a negative regulator of -catenin transcriptional activity; however, its repressive effect is independent of Gro/TLE. Our data suggest that En-1 acts by destabilizing -catenin via a proteasomal degradation pathway that is GSK-3–independent. Moreover, because En-1-mediated -catenin degradation is also Siah independent, our data imply that En-1 exerts its repressive effect by a novel mechanism negatively controlling the level of -catenin.

Address correspondence to: Arnona Gazit ( micro1{at}post.tau.ac.il)

Abbreviations used: APC, adenomatous polyposis coli; Eng, Drosophila Engrailed; En-1, Engrailed-1; Fz, Frizzled; HA, hemagglutinin; -Gal, -galactosidase; GSK, glycogen synthase kinase; Gro, Groucho; LEF/TCF, lymphoid enhancer factor/T-cell factor; TLE, transducin-like enhancer of split; Wg, Wingless.

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