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

Research output: Contribution to journalJournal articleResearchpeer-review

P J Holst, M M Rosenkilde, D Manfra, S C Chen, M T Wiekowski, B Holst, F Cifire, M Lipp, T W Schwartz, S A Lira

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.
Original languageEnglish
JournalJournal of Clinical Investigation
Volume108
Issue number12
Pages (from-to)1789-96
Number of pages7
ISSN0021-9738
DOIs
Publication statusPublished - 2001

Bibliographical note

Keywords: Amino Acid Sequence; Animals; COS Cells; Chemokines; Ligands; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Molecular Sequence Data; Neovascularization, Pathologic; Receptors, Chemokine; Sarcoma, Kaposi; Signal Transduction; Viral Proteins

ID: 10536519