Engrailed-1 negatively regulates beta-catenin transcriptional activity by destabilizing beta-catenin via a glycogen synthase kinase-3beta-independent pathway.

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 beta-catenin from ubiquitination and proteasomal degradation induced by glycogen synthase kinase (GSK)-3beta inhibition. The stabilized beta-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 beta-catenin transcriptional activity; however, its repressive effect is independent of Gro/TLE. Our data suggest that En-1 acts by destabilizing beta-catenin via a proteasomal degradation pathway that is GSK-3beta-independent. Moreover, because En-1-mediated beta-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 beta-catenin.
Mesh Terms:
Base Sequence, Blotting, Northern, Cell Line, Cloning, Molecular, DNA Primers, Gene Expression Regulation, Glycogen Synthase Kinase 3, Homeodomain Proteins, Humans, Molecular Sequence Data, Proteasome Endopeptidase Complex, Recombinant Proteins, Transcription, Genetic, Ubiquitin, beta Catenin
Mol. Biol. Cell
Date: Jun. 01, 2006
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