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Mucosal Immunol. 2012 Nov;5(6):681-90. doi: 10.1038/mi.2012.41. Epub 2012 Jun 13.

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

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  • 1Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory of Medicine, Emory University, Atlanta, GA, USA.

Abstract

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 small interfering RNA-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 glycogen synthase kinase 3β 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.

PMID:
22692453
[PubMed - indexed for MEDLINE]
PMCID:
PMC3481006
Free PMC Article

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