Affiliation:
1. Program in Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Abstract
ABSTRACT
Wnt signaling stabilizes β-catenin, which in turn influences the transcription of Wnt-responsive genes in conjunction with T-cell factor (TCF) transcription factors. At present, there are two models for the actions of β-catenin. The conventional nuclear model suggests that β-catenin acts in the nucleus to form a heterodimeric transcriptional factor complex with TCF, with TCF providing DNA-specific binding and the C and N termini of β-catenin stimulating transcription. The alternative cytoplasmic model postulates that β-catenin exports TCF from the nucleus to relieve its repressive activity or activates it in the cytoplasm. We have generated modified forms of β-catenin and used RNA interference against endogenous β-catenin to distinguish between these models in cultured mammalian and
Drosophila
cells. We show that the VP16 transcriptional activation domain can replace the C terminus of β-catenin without loss of function and that the function of β-catenin is compromised by fusion to a transcriptional repressor domain from histone deacetylase, favoring the direct effects of β-catenin in the nucleus. Furthermore, membrane-tethered β-catenin requires interaction with the adenomatous polyposis coli protein but not with TCF for its function, whereas untethered β-catenin requires binding to TCF for its signaling activity. Importantly, by using RNA interference, we show that the signaling activity of membrane-tethered β-catenin, but not free β-catenin, requires the presence of endogenous β-catenin, which is able to accumulate in the nucleus when stabilized by the binding of the β-catenin degradation machinery to the membrane-tethered form. All of these data support a nuclear model for the normal function of β-catenin.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
69 articles.
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