Document Detail


Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1 alpha to induce vascular endothelial growth factor expression.
MedLine Citation:
PMID:  18339855     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Hypoxia-inducible factor-1 (HIF-1) is the master regulator of both developmental and pathologic angiogenesis, composed of an oxygen-sensitive alpha-subunit and a constitutively expressed beta-subunit. HIF-1 activity in tumors depends on the availability of the HIF-1 alpha subunit, the levels of which are increased under hypoxic conditions. Recent studies have shown that HIF-1 plays an important role in KSHV reactivation from latency and pathogenesis. Here, we report a novel mechanism by which KSHV activates HIF-1 activity. Specific interaction between KSHV viral IFN regulatory factor 3 (vIRF3) and the HIF-1 alpha subunit led to the HIF-1 alpha stabilization and transcriptional activation, which induced vascular endothelial growth factor expression and ultimately facilitated endothelial tube formation. Remarkably, the central domain of vIRF3, containing double alpha-helix motifs, was sufficient not only for binding to HIF-1 alpha but also for blocking its degradation in normoxic conditions. This indicates that KSHV has developed a unique mechanism to enhance HIF-1 alpha protein stability and transcriptional activity by incorporating a viral homologue of cellular IRF gene into its genome, which may contribute to viral pathogenesis.
Authors:
Young C Shin; Chul-Hyun Joo; Michaela U Gack; Hye-Ra Lee; Jae U Jung
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  68     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-14     Completed Date:  2008-04-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1751-9     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA. young_shin@hms.harvard.edu
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Cell Line
Cell Nucleus / metabolism
Endothelium, Vascular / cytology,  metabolism
Herpesvirus 8, Human / genetics,  metabolism*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics,  metabolism*
Interferon Regulatory Factor-3 / genetics,  metabolism*
Molecular Sequence Data
Plasmids / genetics
Up-Regulation
Vascular Endothelial Growth Factor A / biosynthesis*,  genetics
Grant Support
ID/Acronym/Agency:
CA106156/CA/NCI NIH HHS; CA115284/CA/NCI NIH HHS; CA82057/CA/NCI NIH HHS; CA91819/CA/NCI NIH HHS; RR00168/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Interferon Regulatory Factor-3; 0/Vascular Endothelial Growth Factor A

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


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