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Kaposi's Sarcoma-Associated Herpesvirus Viral IFN Regulatory Factor 3 Stabilizes Hypoxia-Inducible Factor-1α to Induce Vascular Endothelial Growth Factor Expression

Cancer research (Chicago, Ill.), 2008-03, Vol.68 (6), p.1751-1759 [Peer Reviewed Journal]

2008 INIST-CNRS ;ISSN: 0008-5472 ;EISSN: 1538-7445 ;DOI: 10.1158/0008-5472.CAN-07-2766 ;PMID: 18339855 ;CODEN: CNREA8

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Title:
Kaposi's Sarcoma-Associated Herpesvirus Viral IFN Regulatory Factor 3 Stabilizes Hypoxia-Inducible Factor-1α to Induce Vascular Endothelial Growth Factor Expression
Author: SHIN, Young C ; JOO, Chul-Hyun ; GACK, Michaela U ; LEE, Hye-Ra ; JUNG, Jae U
Subjects: Amino Acid Sequence ; Antineoplastic agents ; Biological and medical sciences ; Cell Line ; Cell Nucleus - metabolism ; Endothelium, Vascular - cytology ; Endothelium, Vascular - metabolism ; Herpesvirus 8, Human - genetics ; Herpesvirus 8, Human - metabolism ; Human herpesvirus 8 ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Infectious diseases ; Interferon Regulatory Factor-3 - genetics ; Interferon Regulatory Factor-3 - metabolism ; Kaposi's sarcoma-associated herpesvirus ; Medical sciences ; Molecular Sequence Data ; Pharmacology. Drug treatments ; Plasmids - genetics ; Tumors ; Up-Regulation ; Vascular Endothelial Growth Factor A - biosynthesis ; Vascular Endothelial Growth Factor A - genetics ; Viral diseases
Is Part Of: Cancer research (Chicago, Ill.), 2008-03, Vol.68 (6), p.1751-1759
Description: 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.
Publisher: Philadelphia, PA: American Association for Cancer Research
Language: English
Identifier: ISSN: 0008-5472
EISSN: 1538-7445
DOI: 10.1158/0008-5472.CAN-07-2766
PMID: 18339855
CODEN: CNREA8
Source: MEDLINE
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Kaposi's Sarcoma-Associated Herpesvirus Viral IFN Regulatory Factor 3 Stabilizes Hypoxia-Inducible Factor-1α to Induce Vascular Endothelial Growth Factor Expression

2008 INIST-CNRS ;ISSN: 0008-5472 ;EISSN: 1538-7445 ;DOI: 10.1158/0008-5472.CAN-07-2766 ;PMID: 18339855 ;CODEN: CNREA8

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