Requirement for a Nuclear Function of β-Catenin in Wnt Signaling
| Autor: | Liang Schweizer, Feng Cong, Mario Chamorro, Harold E. Varmus |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Beta-catenin
Lymphoid Enhancer-Binding Factor 1 Recombinant Fusion Proteins TCF/LEF family Cell Line Mice Transcription (biology) RNA interference Proto-Oncogene Proteins Animals Humans RNA Messenger Cell Growth and Development Molecular Biology Transcription factor beta Catenin Sequence Deletion Cell Nucleus Base Sequence biology Wnt signaling pathway DNA Cell Biology Zebrafish Proteins Molecular biology Protein Structure Tertiary Cell biology DNA-Binding Proteins Wnt Proteins Cytoskeletal Proteins COS Cells POU Domain Factors NIH 3T3 Cells Trans-Activators biology.protein Drosophila RNA Interference Histone deacetylase Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | Molecular and Cellular Biology. 23:8462-8470 |
| ISSN: | 1098-5549 |
| Popis: | Wnt signaling stabilizes beta-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 beta-catenin. The conventional nuclear model suggests that beta-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 beta-catenin stimulating transcription. The alternative cytoplasmic model postulates that beta-catenin exports TCF from the nucleus to relieve its repressive activity or activates it in the cytoplasm. We have generated modified forms of beta-catenin and used RNA interference against endogenous beta-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 beta-catenin without loss of function and that the function of beta-catenin is compromised by fusion to a transcriptional repressor domain from histone deacetylase, favoring the direct effects of beta-catenin in the nucleus. Furthermore, membrane-tethered beta-catenin requires interaction with the adenomatous polyposis coli protein but not with TCF for its function, whereas untethered beta-catenin requires binding to TCF for its signaling activity. Importantly, by using RNA interference, we show that the signaling activity of membrane-tethered beta-catenin, but not free beta-catenin, requires the presence of endogenous beta-catenin, which is able to accumulate in the nucleus when stabilized by the binding of the beta-catenin degradation machinery to the membrane-tethered form. All of these data support a nuclear model for the normal function of beta-catenin. |
| Databáze: | OpenAIRE |
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