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PMID: 11748262 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity.

The Journal of clinical investigation ·Vol. 108 ·No. 12 ·2001-12-00 ·Pages 1789-96

Holst PJ, Rosenkilde MM, Manfra D, Chen SC, Wiekowski MT, Holst B, Cifire F, Lipp M, Schwartz TW, Lira SA

Abstract

ORF74 (or KSHV-vGPCR) is a highly constitutively active G protein-coupled receptor encoded by HHV8 that is regulated both positively and negatively by endogenous chemokines. When expressed in transgenic mice, this chemokine receptor induces an angioproliferative disease closely resembling Kaposi sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does not respond to agonist stimulation have a much lower incidence of angiogenic lesions and tumors. These results indicate that induction of the KS-like disease in transgenic mice by ORF74 requires not only high constitutive signaling activity but also modulation of this activity by endogenous chemokines.

MeSH Terms
Amino Acid Sequence Animals COS Cells Chemokines/physiology Ligands Mice Mice, Inbred C57BL Mice, Inbred DBA Mice, Transgenic Molecular Sequence Data Neovascularization, Pathologic/etiology Receptors, Chemokine/physiology Sarcoma, Kaposi/etiology,prevention & control Signal Transduction Viral Proteins/physiology
Chemicals
Chemokines Ligands ORF74 protein, Human herpesvirus 8 Receptors, Chemokine Viral Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Holst P J
Laboratory for Molecular Pharmacology, Department of Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Rosenkilde M M
Manfra D
Chen S C
Wiekowski M T
Holst B
Cifire F
Lipp M
Schwartz T W
Lira S A
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI13622
Published
2001-12-00
Pages
1789-96
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC209468
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI13622 PMC Full Text View journal details
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