Lymphoid enhancer factor-1 blocks adenomatous polyposis coli-mediated nuclear export and degradation of beta-catenin. Regulation by histone deacetylase 1
| Autor: | Beric R, Henderson, Melanie, Galea, Stefan, Schuechner, Louie, Leung |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Lymphoid Enhancer-Binding Factor 1
T-Lymphocytes Adenomatous Polyposis Coli Protein Genetic Vectors Active Transport Cell Nucleus 3T3 Cells Cadherins Transfection Histone Deacetylases Recombinant Proteins DNA-Binding Proteins Cytoskeletal Proteins Kinetics Mice Genes Reporter Colonic Neoplasms Trans-Activators Tumor Cells Cultured Animals Humans Luciferases beta Catenin DNA Primers Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 277(27) |
| ISSN: | 0021-9258 |
| Popis: | The oncogenic protein beta-catenin is overexpressed in many cancers, frequently accumulating in nuclei where it forms active complexes with lymphoid enhancer factor-1 (LEF-1)/T-cell transcription factors, inducing genes such as c-myc and cyclin D1. In normal cells, nuclear beta-catenin levels are controlled by the adenomatous polyposis coli (APC) protein through nuclear export and cytoplasmic degradation. Transient expression of LEF-1 is known to increase nuclear beta-catenin levels by an unknown mechanism. Here, we show that APC and LEF-1 compete for nuclear beta-catenin with opposing consequences. APC can export nuclear beta-catenin to the cytoplasm for degradation. In contrast, LEF-1 anchors beta-catenin in the nucleus by blocking APC-mediated nuclear export. LEF-1 also prevented the APC/CRM1-independent nuclear export of beta-catenin as revealed by in vitro assays. Importantly, LEF-1-bound beta-catenin was protected from degradation by APC and axin in SW480 colon cancer cells. The ability of LEF-1 to trap beta-catenin in the nucleus was down-regulated by histone deacetylase 1, and this correlated with a decrease in LEF1 transcription activity. Our findings identify LEF-1 as key regulator of beta-catenin nuclear localization and stability and suggest that overexpression of LEF-1 in colon cancer and melanoma cells may contribute to the accumulation of oncogenic beta-catenin in the nucleus. |
| Databáze: | OpenAIRE |
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