Journal
MUCOSAL IMMUNOLOGY
Volume 5, Issue 6, Pages 681-690Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2012.41
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Funding
- National Institutes of Health [DK64399, DK55679, DK59888]
- Crohn's and Colitis Foundation of America Fellowship
- German Research Association [STU 238/6-1]
- Crohn's & Colitis Foundation of America [2634] Funding Source: researchfish
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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 beta-catenin/T cell factor (TCF) signaling. Interestingly, proinflammatory cytokine-induced GBP-1 was found to be a potent suppressor of beta-catenin protein levels and beta-catenin serine 552 phosphorylation. Neither glycogen synthase kinase 3 beta nor proteasomal inhibition alleviated GBP-1-mediated suppression of cell proliferation or beta-catenin/TCF signaling, indicating a non-canonical mechanism of beta-catenin inhibition. Together, these data show that cytokine-induced GBP-1 retards cell proliferation by forming a negative feedback loop that suppresses beta-catenin/TCF signaling.
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