IFN-γ and TNF-α induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling

Proinflammatory cytokines induce Guanylate Binding Protein 1 (GBP-1) protein expression in intestinal epithelial tissues. GBP-1 has been described as influencing a number of cellular processes important for epithelial homeostasis, including cell proliferation. However, many questions remain as to the role of GBP-1 in intestinal mucosal homeostasis. We therefore sought to investigate the function of proinflammatory cytokine induced GBP-1 during intestinal epithelial cell proliferation. Through the use of complementary GBP-1 overexpression and siRNA-mediated knockdown studies, we now show that GBP-1 acts to inhibit pro-mitogenic β-catenin/T cell factor (TCF) signaling. Interestingly, proinflammatory cytokine induced GBP-1 was found to be a potent suppressor of β-catenin protein levels and β-catenin serine 552 phosphorylation. Neither GSK3-β nor proteasomal inhibition alleviated GBP-1-mediated suppression of cell proliferation or β- catenin/TCF signaling, indicating a non-canonical mechanism of β-catenin inhibition. Together, these data show that cytokine-induced GBP-1 retards cell proliferation by forming a negative feedback loop that suppresses β-catenin/TCF signaling.