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 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.
Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory of Medicine, Emory University, Atlanta, GA, USA.
C T
CT
Capaldo
N
N
Beeman
R S
RS
Hilgarth
P
P
Nava
N A
NA
Louis
E
E
Naschberger
M
M
Stürzl
C A
CA
Parkos
A
A
Nusrat
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
C495270:CTNNB1 protein, human; C490287:GBP1 protein, human; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D012694:Serine; D007371:Interferon-gamma; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins