Interactions Between β-Catenin and Transforming Growth Factor-β Signaling Pathways Mediate Epithelial-Mesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)*
| Autor: | Hongjun Wang, Yixin Liu, Zea Borok, Per Flodby, Janice M. Liebler, David K. Ann, Cu Nguyen, Parviz Minoo, Michael Kahn, Beiyun Zhou, Qian Zhong, Edward D. Crandall, Arum Han, Manda S. Krishnaveni |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Beta-catenin
Epithelial-Mesenchymal Transition Pulmonary Fibrosis Pyrimidinones CREB Biochemistry Cell Line Transforming Growth Factor beta1 Humans Smad3 Protein CREB-binding protein Molecular Biology beta Catenin Cell Proliferation biology Wnt signaling pathway Molecular Bases of Disease Epithelial Cells Cell Biology Bridged Bicyclo Compounds Heterocyclic CREB-Binding Protein Actins Gene Expression Regulation Catenin Cancer research biology.protein Signal transduction Chromatin immunoprecipitation Transforming growth factor Signal Transduction |
| Popis: | Interactions between transforming growth factor-β (TGF-β) and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes (differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition (EMT)) and precise mechanisms in many cases remain unknown. We investigated β-catenin-dependent and transforming growth factor-β1 (TGF-β1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary fibrosis. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the β-catenin/CBP (but not β-catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-β1-mediated α-smooth muscle actin (α-SMA) and collagen induction in AEC. We now demonstrate that TGF-β1 induces LEF/TCF TOPFLASH reporter activation and nuclear β-catenin accumulation, while LiCl augments TGF-β-induced α-SMA expression, further confirming co-operation between β-catenin- and TGF-β-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of β-catenin and overexpression of ICAT abrogated effects of TGF-β1 on α-SMA transcription/expression, indicating a requirement for β-catenin in these Smad3-dependent effects. Following TGF-β treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and β-catenin, while chromatin immunoprecipitation (ChIP)-re-ChIP identified spatial and temporal regulation of α-SMA via complex formation among Smad3, β-catenin, and CBP. ICG-001 inhibited α-SMA expression/transcription in response to TGF-β as well as α-SMA promoter occupancy by β-catenin and CBP, demonstrating a previously unknown requisite TGF-β1/β-catenin/CBP-mediated pro-EMT signaling pathway. Clinical relevance was shown by β-catenin/Smad3 co-localization and CBP expression in AEC of IPF patients. These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-β. |
| Databáze: | OpenAIRE |
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