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PMID: 17611605 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A post-transcriptional pathway represses monocyte VEGF-A expression and angiogenic activity.

The EMBO journal ·Vol. 26 ·No. 14 ·2007-07-25 ·Pages 3360-72

Ray PS, Fox PL

Abstract

Monocyte-macrophage activation by interferon (IFN)-gamma is a key initiating event in inflammation. Usually, the macrophage response is self-limiting and inflammation resolves. Here, we describe a mechanism by which IFN-gamma contributes to inflammation resolution by suppressing expression of vascular endothelial growth factor-A (VEGF-A), a macrophage product that stimulates angiogenesis during chronic inflammation and tumorigenesis. VEGF-A was identified as a candidate target of the IFN-gamma-activated inhibitor of translation (GAIT) complex by bioinformatic analysis, and experimentally validated by messenger RNA-protein interaction studies. Although IFN-gamma induced persistent VEGF-A mRNA expression, translation was suppressed by delayed binding of the GAIT complex to a specific element delineated in the 3'UTR. Translational silencing resulted in decreased VEGF-A synthesis and angiogenic activity. Our results describe a unique anti-inflammatory pathway in which IFN-gamma-dependent induction of VEGF-A mRNA is translationally silenced by the same stimulus, and they suggest the GAIT system directs a post-transcriptional operon that contributes to inflammation resolution.

MeSH Terms
3' Untranslated Regions/metabolism Animals Base Sequence Cattle Gene Expression Regulation/drug effects Gene Silencing/drug effects Humans Interferon-gamma/pharmacology Molecular Sequence Data Monocytes/cytology,drug effects,metabolism Neovascularization, Physiologic/drug effects Nucleic Acid Conformation/drug effects Protein Biosynthesis/drug effects RNA, Messenger/genetics,metabolism Regulatory Sequences, Nucleic Acid/genetics Transcription, Genetic/drug effects Vascular Endothelial Growth Factor A/genetics,metabolism
Chemicals
3' Untranslated Regions RNA, Messenger VEGFA protein, human Vascular Endothelial Growth Factor A Interferon-gamma
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Ray Partho Sarothi
Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Fox Paul L
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7601774
Published
2007-07-25
Epub
2007-00-05
Pages
3360-72
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1933405
Subset
IM
Grants
NHLBI NIH HHS · P01 HL076491 · United States
NHLBI NIH HHS · P01 HL029582 · United States
NHLBI NIH HHS · HL76491 · United States
NHLBI NIH HHS · HL29582 · United States
NHLBI NIH HHS · R01 HL067725 · United States
NHLBI NIH HHS · HL67725 · United States
External Links
PubMed source DOI: 10.1038/sj.emboj.7601774 PMC Full Text View journal details
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