PubMed | New York Harbor Healthcare System New York, NYU Langone Medical Center, Mount Sinai School of Medicine, University of Texas M. D. Anderson Cancer Center and New York University
Type: Journal Article | Journal: American journal of cancer research | Year: 2014
Transcriptional intermediary factor 1 gamma (Tif1) (Ectodermin/PTC7/RFG7/TRIM33) is a transcriptional cofactor with an important role in the regulation of the TGF pathway. It has been suggested that it competes with Smad2/Smad3 for binding to Smad4, or alternatively that it may target Smad4 for degradation, although its role in carcinogenesis is unclear. In this study, we showed that Tif1 interacts with Smad1/Smad4 complex in vivo, using both yeast two-hybrid and coimmunoprecipitation assays. We demonstrated that Tif1 inhibits transcriptional activity of the Smad1/Smad4 complex through its PHD domain or bromo-domainin pancreatic cells by luciferase assay. Additionally, there is a dynamic inverse relationship between the levels of Tif1 and Smad4 in benign and malignant pancreatic cell lines. Overexpression of Tif1 resulted in decreased level of Smad4. Both overexpression and knockdown of Tif1 resulted in growth inhibition in both benign and cancerous pancreatic cell lines, attributable to a G2-phase cell cycle arrest, but only knockdown of Tif1 reduces tumor cell invasiveness in vitro. Our study demonstrated that imbalanced expression of Tif1 results in inhibition of pancreatic ductal epithelial cell growth. In addition, knockdown of Tif1 may inhibit tumor invasion. These data suggest that Tif1 might serve as a potential therapeutic target for pancreatic cancer.