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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).

http://www.ncbi.nlm.nih.gov/pubmed/22241478

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.

Pubmed ID: 22241478 RIS Download

Mesh terms: Actins | Bicyclo Compounds, Heterocyclic | CREB-Binding Protein | Cell Line | Cell Proliferation | Epithelial Cells | Epithelial-Mesenchymal Transition | Gene Expression Regulation | Humans | Pulmonary Fibrosis | Pyrimidinones | Signal Transduction | Smad3 Protein | Transforming Growth Factor beta1 | beta Catenin

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Associated grants

  • Agency: NIDCR NIH HHS, Id: DE010742
  • Agency: NIDCR NIH HHS, Id: DE014183
  • Agency: NIEHS NIH HHS, Id: ES017034
  • Agency: NIEHS NIH HHS, Id: ES018782
  • Agency: NHLBI NIH HHS, Id: HL038578
  • Agency: NHLBI NIH HHS, Id: HL038621
  • Agency: NHLBI NIH HHS, Id: HL056590
  • Agency: NHLBI NIH HHS, Id: HL062569
  • Agency: NHLBI NIH HHS, Id: HL073722
  • Agency: NHLBI NIH HHS, Id: HL089445
  • Agency: NHLBI NIH HHS, Id: HL095349
  • Agency: PHS HHS, Id: NEI03040
  • Agency: NCI NIH HHS, Id: P30 CA014089
  • Agency: NIDDK NIH HHS, Id: P30 DK048522
  • Agency: NHLBI NIH HHS, Id: R01 HL112638
  • Agency: NHLBI NIH HHS, Id: R37 HL062569

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