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

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Official URL:https://doi.org/10.1172/JCI13622
PubMed:View item in PubMed
Creators Name:Holst, P.J. and Rosenkilde, M.M. and Manfra, D. and Chen, S.C. and Wiekowski, M.T. and Holst, B. and Cifire, F. and Lipp, M. and Schwartz, T.W. and Lira, S.A.
Journal Title:Journal of Clinical Investigation
Journal Abbreviation:J Clin Invest
Page Range:1789-1796
Date:December 2001
Keywords:Amino Acid Sequence, COS Cells, Chemokines, Ligands, Molecular Sequence Data, Pathologic Neovascularization, Chemokine Receptors, Kaposi Sarcoma, Signal Transduction, Viral Proteins, Animals, Mice
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.
Publisher:American Society for Clinical Investigation (U.S.A.)
Item Type:Article

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