Linked Life Data

18281687

Source:http://linkedlifedata.com/resource/pubmed/id/18281687

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
18
pubmed:dateCreated
2008-4-28
pubmed:abstractText
The proinflammatory cytokine interleukin (IL)-1 activates several hundred genes within the same cell. This occurs in part by activation of the MKK7-JNK-c-Jun signaling pathway whose precise role in the regulation of individual inflammatory genes is still incompletely understood. To identify the genes that are under specific control of activated JNK, we used a JNK-MKK7 fusion protein. Genome-wide microarray analysis revealed EGR-1 as the transcript that was most strongly induced by JNK-MKK7. IL-1-stimulated EGR-1 mRNA and protein expression were impaired in cells lacking JNK or c-Jun. Transcriptional activation of the EGR-1 promoter by JNK-MKK7 or by IL-1 required a single upstream AP-1 site and three distal serum-response elements (SRE). Reconstitution experiments in c-Jun-deficient cells revealed that c-Jun is required for EGR-1 transcription through both the AP-1 site and the distal SREs. By chromatin immunoprecipitation analysis, we found IL-1-inducible recruitment of c-Jun to the AP-1 site and to the region containing the three distal SREs. These experiments suggest that c-Jun plays a dual role in EGR-1 transcription. It directly binds to the AP-1 element, and at the same time it is essential for promoter activation through the three distal SREs by an indirect unknown mechanism. As predicted by TRANSFAC analysis and verified by ChIP experiments, IL-1-induced EGR-1 protein binds to the promoter regions of inflammatory mediators such as IL-6, IL-8, and CCL2. Furthermore, short interfering RNA-mediated suppression of EGR-1 partially suppresses IL-1-inducible transcription of IL-8, IL-6, and CCL2. In summary, we provide novel evidence for a complex c-Jun-mediated mechanism that is essential for inducible EGR-1 expression. We identify this pathway as a previously unrecognized part of a multistep gene regulatory network that controls cytokine and chemokine expression via the IL-1-MKK7-JNK-c-Jun-EGR-1 pathway.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
2
pubmed:volume
283
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
12120-8
pubmed:dateRevised
2011-5-25
pubmed:meshHeading
pubmed-meshheading:18281687-Animals, pubmed-meshheading:18281687-Base Sequence, pubmed-meshheading:18281687-Binding Sites, pubmed-meshheading:18281687-Cell Line, pubmed-meshheading:18281687-Chemokine CCL2, pubmed-meshheading:18281687-Chromatin Immunoprecipitation, pubmed-meshheading:18281687-Early Growth Response Protein 1, pubmed-meshheading:18281687-Gene Expression Regulation, pubmed-meshheading:18281687-Genome, Human, pubmed-meshheading:18281687-Humans, pubmed-meshheading:18281687-Interleukin-1, pubmed-meshheading:18281687-Interleukin-6, pubmed-meshheading:18281687-Interleukin-8, pubmed-meshheading:18281687-JNK Mitogen-Activated Protein Kinases, pubmed-meshheading:18281687-MAP Kinase Kinase 7, pubmed-meshheading:18281687-MAP Kinase Signaling System, pubmed-meshheading:18281687-Mice, pubmed-meshheading:18281687-Models, Genetic, pubmed-meshheading:18281687-Molecular Sequence Data, pubmed-meshheading:18281687-Phosphorylation, pubmed-meshheading:18281687-Protein Binding, pubmed-meshheading:18281687-Proto-Oncogene Proteins c-jun, pubmed-meshheading:18281687-RNA, Messenger, pubmed-meshheading:18281687-Transcription, Genetic, pubmed-meshheading:18281687-Transcription Factor AP-1
pubmed:year
2008
pubmed:articleTitle
Transcriptional regulation of EGR-1 by the interleukin-1-JNK-MKK7-c-Jun pathway.
pubmed:affiliation
Institute of Pharmacology, Medical School Hannover, D-30625 Hannover, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't