Document Detail


A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-κB signaling pathways.
MedLine Citation:
PMID:  23322906     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cytoplasmic receptor NOD2 (nucleotide-binding oligomerization domain 2) senses peptidoglycan fragments and triggers host defense pathways, including activation of nuclear factor κB (NF-κB) signaling, which lead to inflammatory immune responses. Dysregulation of NOD2 signaling is associated with inflammatory diseases, such as Crohn's disease and Blau syndrome. We used a genome-wide small interfering RNA screen to identify regulators of the NOD2 signaling pathway. Several genes associated with Crohn's disease risk were identified in the screen. A comparison of candidates from this screen with other "omics" data sets revealed interconnected networks of genes implicated in NF-κB signaling, thus supporting a role for NOD2 and NF-κB pathways in the pathogenesis of Crohn's disease. Many of these regulators were validated in secondary assays, such as measurement of interleukin-8 secretion, which is partially dependent on NF-κB. Knockdown of putative regulators in human embryonic kidney 293 cells followed by stimulation with tumor necrosis factor-α revealed that most of the genes identified were general regulators of NF-κB signaling. Overall, the genes identified here provide a resource to facilitate the elucidation of the molecular mechanisms that regulate NOD2- and NF-κB-mediated inflammation.
Authors:
Neil Warner; Aaron Burberry; Luigi Franchi; Yun-Gi Kim; Christine McDonald; Maureen A Sartor; Gabriel Núñez
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-15
Journal Detail:
Title:  Science signaling     Volume:  6     ISSN:  1937-9145     ISO Abbreviation:  Sci Signal     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-16     Completed Date:  2013-06-28     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  101465400     Medline TA:  Sci Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  rs3     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acetylmuramyl-Alanyl-Isoglutamine / pharmacology
Animals
Blotting, Western
Bone Marrow Cells / cytology,  drug effects,  metabolism
Cell Survival / genetics
Cells, Cultured
Crohn Disease / genetics
Gene Expression Regulation / drug effects
Gene Regulatory Networks / drug effects
Genome, Human / genetics*
HEK293 Cells
Humans
I-kappa B Proteins / metabolism
Macrophages / cytology,  drug effects,  metabolism
Mice
Mice, Knockout
Mitogen-Activated Protein Kinases / metabolism
Models, Genetic
NADPH Oxidase / deficiency,  genetics
NF-kappa B / genetics*,  metabolism
Nod2 Signaling Adaptor Protein / genetics*,  metabolism
RNA Interference
RNA, Small Interfering / genetics*
Signal Transduction / drug effects,  genetics*
Tumor Necrosis Factor-alpha / pharmacology
Grant Support
ID/Acronym/Agency:
2R01DK61707/DK/NIDDK NIH HHS; R01 DK050984/DK/NIDDK NIH HHS; R01 DK061707/DK/NIDDK NIH HHS; R01 DK082437/DK/NIDDK NIH HHS; R01DK050984/DK/NIDDK NIH HHS; R01DK082437/DK/NIDDK NIH HHS; UL1 RR024986/RR/NCRR NIH HHS; UL1RR024986/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/I-kappa B Proteins; 0/NF-kappa B; 0/NOD2 protein, human; 0/Nod2 Signaling Adaptor Protein; 0/RNA, Small Interfering; 0/Tumor Necrosis Factor-alpha; 53678-77-6/Acetylmuramyl-Alanyl-Isoglutamine; EC 1.6.3.1/NADPH Oxidase; EC 1.6.3.1/neutrophil cytosolic factor 1; EC 2.7.11.24/Mitogen-Activated Protein Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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