|A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-κB signaling pathways.|
|PMID: 23322906 Owner: NLM Status: MEDLINE|
|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.|
|Neil Warner; Aaron Burberry; Luigi Franchi; Yun-Gi Kim; Christine McDonald; Maureen A Sartor; Gabriel Núñez|
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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2013-01-15|
|Title: Science signaling Volume: 6 ISSN: 1937-9145 ISO Abbreviation: Sci Signal Publication Date: 2013 Jan|
|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|
|Languages: eng Pagination: rs3 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Bone Marrow Cells / cytology, drug effects, metabolism
Cell Survival / genetics
Crohn Disease / genetics
Gene Expression Regulation / drug effects
Gene Regulatory Networks / drug effects
Genome, Human / genetics*
I-kappa B Proteins / metabolism
Macrophages / cytology, drug effects, metabolism
Mitogen-Activated Protein Kinases / metabolism
NADPH Oxidase / deficiency, genetics
NF-kappa B / genetics*, metabolism
Nod2 Signaling Adaptor Protein / genetics*, metabolism
RNA, Small Interfering / genetics*
Signal Transduction / drug effects, genetics*
Tumor Necrosis Factor-alpha / pharmacology
|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|
|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 18.104.22.168/NADPH Oxidase; EC 22.214.171.124/neutrophil cytosolic factor 1; EC 126.96.36.199/Mitogen-Activated Protein Kinases|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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