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Molecular and Cellular Biology, December 2003, p. 8462-8470, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8462-8470.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Requirement for a Nuclear Function of ß-Catenin in Wnt Signaling

Feng Cong, Liang Schweizer, Mario Chamorro, and Harold Varmus*

Program in Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Received 13 June 2003/ Returned for modification 14 August 2003/ Accepted 3 September 2003

Wnt signaling stabilizes ß-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 ß-catenin. The conventional nuclear model suggests that ß-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 ß-catenin stimulating transcription. The alternative cytoplasmic model postulates that ß-catenin exports TCF from the nucleus to relieve its repressive activity or activates it in the cytoplasm. We have generated modified forms of ß-catenin and used RNA interference against endogenous ß-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 ß-catenin without loss of function and that the function of ß-catenin is compromised by fusion to a transcriptional repressor domain from histone deacetylase, favoring the direct effects of ß-catenin in the nucleus. Furthermore, membrane-tethered ß-catenin requires interaction with the adenomatous polyposis coli protein but not with TCF for its function, whereas untethered ß-catenin requires binding to TCF for its signaling activity. Importantly, by using RNA interference, we show that the signaling activity of membrane-tethered ß-catenin, but not free ß-catenin, requires the presence of endogenous ß-catenin, which is able to accumulate in the nucleus when stabilized by the binding of the ß-catenin degradation machinery to the membrane-tethered form. All of these data support a nuclear model for the normal function of ß-catenin.

* Corresponding author. Mailing address: Memorial Sloan-Kettering Cancer Center, 430 East 67th St., RRL 711, New York, NY 10021. Phone: (212) 639-6193. Fax: (212) 717-3125. E-mail: varmus{at}mskcc.org.

Molecular and Cellular Biology, December 2003, p. 8462-8470, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8462-8470.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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