title: Imbalanced expression of Tif1γ inhibits pancreatic ductal epithelial cell growth.
abstract: Transcriptional intermediary factor 1 gamma (Tif1γ) (Ectodermin/PTC7/RFG7/TRIM33) is a transcriptional cofactor with an important role in the regulation of the TGFβ 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 Tif1γ interacts with Smad1/Smad4 complex in vivo, using both yeast two-hybrid and coimmunoprecipitation assays. We demonstrated that Tif1γ 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 Tif1γ and Smad4 in benign and malignant pancreatic cell lines. Overexpression of Tif1γ resulted in decreased level of Smad4. Both overexpression and knockdown of Tif1γ resulted in growth inhibition in both benign and cancerous pancreatic cell lines, attributable to a G2-phase cell cycle arrest, but only knockdown of Tif1γ reduces tumor cell invasiveness in vitro. Our study demonstrated that imbalanced expression of Tif1γ results in inhibition of pancreatic ductal epithelial cell growth. In addition, knockdown of Tif1γ may inhibit tumor invasion. These data suggest that Tif1γ might serve as a potential therapeutic target for pancreatic cancer.
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA.
authors: Martin
authors: M
authors: Ligr
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA.
authors: Xinyu
authors: X
authors: Wu
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA.
authors: Garrett
authors: G
authors: Daniels
authors: Department of Pathology, Mount Sinai School of Medicine New York, NY, USA.
authors: David
authors: D
authors: Zhang
authors: Department of Pathology, The University of Texas M.D. Anderson Cancer Center Houston, TX, USA.
authors: Huamin
authors: H
authors: Wang
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA.
authors: Cristina
authors: C
authors: Hajdu
authors: NYU Cancer Institute, New York University Langone Medical Center New York, NY, USA.
authors: Jinhua
authors: J
authors: Wang
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA.
authors: Ruimin
authors: R
authors: Pan
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA.
authors: Zhiheng
authors: Z
authors: Pei
authors: Department of Pathology, The University of Texas M.D. Anderson Cancer Center Houston, TX, USA.
authors: Lanjing
authors: L
authors: Zhang
authors: Department of Pathology, Mount Sinai School of Medicine New York, NY, USA.
authors: Marcovalerio
authors: M
authors: Melis
authors: New York Harbor Healthcare System New York, NY, USA.
authors: Matthew R
authors: MR
authors: Pincus
authors: Department of Surgery, New York University Langone Medical Center New York, NY, USA.
authors: John K
authors: JK
authors: Saunders
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA ; Department of Urology, New York University Langone Medical Center New York, NY, USA ; NYU Cancer Institute, New York University Langone Medical Center New York, NY, USA ; New York Harbor Healthcare System New York, NY, USA.
authors: Peng
authors: P
authors: Lee
authors: Department of Pathology, New York University Langone Medical Center New York, NY, USA.
authors: Ruliang
authors: R
authors: Xu
keywords: Smad; Transcriptional intermediary factor 1 gamma (Tif1γ); pancreatic cancer