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1.
Mucosal Immunol ; 5(6): 681-90, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22692453

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 ß-catenin/T cell factor (TCF) signaling. Interestingly, proinflammatory cytokine-induced GBP-1 was found to be a potent suppressor of ß-catenin protein levels and ß-catenin serine 552 phosphorylation. Neither glycogen synthase kinase 3ß nor proteasomal inhibition alleviated GBP-1-mediated suppression of cell proliferation or ß-catenin/TCF signaling, indicating a non-canonical mechanism of ß-catenin inhibition. Together, these data show that cytokine-induced GBP-1 retards cell proliferation by forming a negative feedback loop that suppresses ß-catenin/TCF signaling.


Subject(s)
Epithelial Cells/metabolism , GTP-Binding Proteins/genetics , Interferon-gamma/pharmacology , TCF Transcription Factors/antagonists & inhibitors , Tumor Necrosis Factor-alpha/pharmacology , beta Catenin/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Epithelial Cells/drug effects , Epithelial Cells/immunology , Feedback, Physiological/drug effects , GTP-Binding Proteins/antagonists & inhibitors , GTP-Binding Proteins/immunology , Gene Expression/drug effects , Gene Expression/immunology , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/immunology , Glycogen Synthase Kinase 3 beta , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Phosphorylation , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/immunology , Protein Kinase Inhibitors/pharmacology , RNA, Small Interfering/genetics , Serine/metabolism , Signal Transduction/drug effects , TCF Transcription Factors/genetics , TCF Transcription Factors/immunology , beta Catenin/genetics , beta Catenin/immunology
2.
Cell Death Dis ; 3: e273, 2012 Feb 23.
Article in English | MEDLINE | ID: mdl-22361748

ABSTRACT

Disruption of tight junctions is often seen during pathogen infection, inflammation, and tumor progression. Mislocalization of the tight junction proteins occludin and claudin in mammary epithelial monolayers leads to apoptosis through the extrinsic pathway. To further investigate the mechanism of this response, a normal mammary epithelial cell line (EpH4) as well as primary mammary epithelial cells were treated with a claudin-disrupting mimic peptide, DFYNP (aspartic acid-phenylalanine-tyrosine-asparagine-proline). Using fluorescent indicators, we found that caspase-3 activation, resulting from treatment with DFYNP, was restricted to EpH4 and primary mammary epithelial cells with mislocalized claudin-4. Mislocalized claudin-4 and occludin were colocalized in non-junctional puncta, and both molecules were found in the death-inducing signaling complex (DISC) where they colocalized with Fas, fas-associated protein with death domain (FADD), active caspase-8 and caspase-3 at distinct apical domains. Importantly, caspase-3 activation was totally repressed in primary mammary epithelial cells from occludin null mice. Thus, the apoptotic response appears to be initiated by the movement of occludin to the DISC suggesting that this molecule has signaling properties that initiate cell death when its tight junction location is disrupted.


Subject(s)
Apoptosis/genetics , Claudins/genetics , Death Domain Receptor Signaling Adaptor Proteins/metabolism , Epithelial Cells/metabolism , Mammary Glands, Animal/metabolism , Membrane Proteins/genetics , Animals , Apoptosis/drug effects , Caspase 3/genetics , Caspase 3/metabolism , Caspase 8/genetics , Caspase 8/metabolism , Claudin-4 , Claudins/metabolism , Death Domain Receptor Signaling Adaptor Proteins/genetics , Epithelial Cells/cytology , Epithelial Cells/drug effects , Fas-Associated Death Domain Protein/genetics , Fas-Associated Death Domain Protein/metabolism , Female , Gene Expression/drug effects , Humans , Mammary Glands, Animal/cytology , Mammary Glands, Animal/drug effects , Membrane Proteins/deficiency , Mice , Mice, Knockout , Occludin , Oligopeptides/pharmacology , Primary Cell Culture , Signal Transduction/drug effects , Tight Junctions/drug effects , Tight Junctions/metabolism , Tight Junctions/pathology , fas Receptor/genetics , fas Receptor/metabolism
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