The murine gastrin promoter is synergistically activated by transforming growth factor-beta/Smad and Wnt signaling pathways

Shi Lei, Alexander Dubeykovskiy, Abhijit Chakladar, Lindsay Wojtukiewicz, Timothy C Wang
Journal of Biological Chemistry 2004 October 8, 279 (41): 42492-502
The transforming growth factor-beta (TGF-beta) and Wnt/wingless pathways play critical roles in the specification of cell fate during development and also contribute to cancer formation and progression. Whereas Wnt signaling is clearly pro-oncogenic, TGF-beta signaling is cell- and context-dependent, manifesting both inhibitory and proliferative effects. The growth factor, gastrin, has previously been shown to be a downstream target of the Wnt pathway and a promoter of gastrointestinal cancer. In this study, we show that the mouse gastrin promoter is regulated synergistically by TGF-beta/Smads and beta-catenin/T-cell factor (TCF). Co-transfection of Smad3/Smad4 and beta-catenin expression constructs synergistically activated mouse gastrin promoter activity 30-60-fold in AGS cells with minimal effect seen with either construct alone. This activation was further potentiated by TGF-beta1 treatment. Mutating either the TCF binding site or the Smad-binding element (SBE) diminished the activation of gastrin expression by Smad3/Smad4 and beta-catenin and led to a loss of gastrin promoter responsiveness to TGF-beta1 treatment. Wnt and TGF-beta regulated endogenous gastrin mRNA levels in AGS cells in a similar fashion, as revealed by small interference RNA studies or overexpression of Smads and TCF4/beta-catenin. Electrophoretic mobility shift assays and DNA affinity precipitation assays showed that the putative SBE and T-cell factor (TCF) sites were able to bind a complex containing Smads and beta-catenin/TCF4. In addition, the synergy between Smads and beta-catenin/TCF4 was dependent on CREB-binding protein (CBP)/P300, as demonstrated by overexpression of CBP or E1A. Moreover, by using a heterogeneous promoter reporter system, we showed that this complex containing Smads/TCF4/beta-catenin complex was able to up-regulate transcription at isolated SBE or TCF sites. Thus, the Wnt signaling pathway is able to activate some target genes through its actions as a co-activator at non-TCF sites and has the potential to profoundly alter transcriptional responses to TGF-beta signaling.

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