Interactions Between -Catenin and Transforming Growth Factor- Signaling Pathways Mediate EpithelialMesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)

TitleInteractions Between -Catenin and Transforming Growth Factor- Signaling Pathways Mediate EpithelialMesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)
Publication TypeJournal Article
Year of Publication2011
AuthorsZhou B, Liu Y, Kahn M, Ann DK, Han A, Wang H, Nguyen C, Flodby P, Zhong Q, Krishnaveni M, Liebler JM, Minoo P, Crandall ED, Borok Z
JournalThe Journal of Biological Chemistry
Volume287
Start Page726
Pagination726-738
Date Published03/2012
Abstract

Interactions between transforming growth factor- (TGF-) 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 -catenin-dependent and transforming growth factor-1 (TGF-1) 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 -catenin/CBP (but not -catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-1-mediated -smooth muscle actin (-SMA) and collagen induction in AEC. We now demonstrate that TGF-1 induces LEF/TCF TOPFLASH reporter activation and nuclear -catenin accumulation, while LiCl augments TGF--induced -SMA expression, further confirming co-operation between -catenin- and TGF--dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of -catenin and overexpression of ICAT abrogated effects of TGF-1 on -SMA transcription/expression, indicating a requirement for -catenin in these Smad3-dependent effects. Following TGF- treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and -catenin, while chromatin immunoprecipitation (ChIP)- re-ChIP identified spatial and temporal regulation of-SMAvia complex formation among Smad3, -catenin, and CBP. ICG- 001 inhibited -SMA expression/transcription in response to TGF- as well as -SMA promoter occupancy by -catenin and CBP, demonstrating a previously unknown requisite TGF-1/ -catenin/CBP-mediated pro-EMT signaling pathway. Clinical relevance was shown by -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/ca