Requirement for a nuclear function of β-catenin in WNT signaling Journal Article
| Authors: | Cong, F.; Schweizer, L.; Chamorro, M.; Varmus, H. |
| Article Title: | Requirement for a nuclear function of β-catenin in WNT signaling |
| 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. |
| Keywords: | signal transduction; controlled study; unclassified drug; dna-binding proteins; proto-oncogene proteins; sequence deletion; nonhuman; protein domain; protein function; animal cell; mammalia; animals; mice; complex formation; carboxy terminal sequence; protein dna binding; transcription initiation; cell line; transcription factor; drosophila; rna interference; cos cells; animalia; transcription factors; dna; amino terminal sequence; genetic transfection; recombinant fusion proteins; rna, messenger; nucleotide sequence; cytoplasm; base sequence; binding site; protein structure, tertiary; trans-activators; cell nucleus; wnt proteins; beta catenin; wnt protein; nih 3t3 cells; histone deacetylase; adenomatous polyp; lymphoid enhancer-binding factor 1; cytoskeletal proteins; mammal cell; insect cell; zebrafish proteins; insecta; humans; priority journal; article; t cell factor; pou domain factors |
| Journal Title: | Molecular and Cellular Biology |
| Volume: | 23 |
| Issue: | 23 |
| ISSN: | 0270-7306 |
| Publisher: | American Society for Microbiology |
| Date Published: | 2003-12-01 |
| Start Page: | 8462 |
| End Page: | 8470 |
| Language: | English |
| DOI: | 10.1128/mcb.23.23.8462-8470.2003 |
| PUBMED: | 14612392 |
| PROVIDER: | scopus |
| PMCID: | PMC262677 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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