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Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1 alpha to induce vascular endothelial growth factor expression.
- Source :
-
Cancer research [Cancer Res] 2008 Mar 15; Vol. 68 (6), pp. 1751-9. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Amino Acid Sequence
Cell Line
Cell Nucleus metabolism
Endothelium, Vascular cytology
Endothelium, Vascular metabolism
Herpesvirus 8, Human genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Interferon Regulatory Factor-3 genetics
Molecular Sequence Data
Plasmids genetics
Up-Regulation
Vascular Endothelial Growth Factor A genetics
Herpesvirus 8, Human metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Interferon Regulatory Factor-3 metabolism
Vascular Endothelial Growth Factor A biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 68
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 18339855
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-07-2766