Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity
Peter J. Holst, … , Thue W. Schwartz, Sergio A. Lira
Peter J. Holst, … , Thue W. Schwartz, Sergio A. Lira
Published December 15, 2001
Citation Information: J Clin Invest. 2001;108(12):1789-1796. https://doi.org/10.1172/JCI13622.
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Article

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

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.

Authors

Peter J. Holst, Mette M. Rosenkilde, Denise Manfra, Shu-Cheng Chen, Maria T. Wiekowski, Birgitte Holst, Felix Cifire, Martin Lipp, Thue W. Schwartz, Sergio A. Lira

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Figure 2

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Generation and expression analysis of ORF74 transgenic mice. (a) Schemat...
Generation and expression analysis of ORF74 transgenic mice. (a) Schematic description of the transgenes CDVG, L91D, Δ22, and R2H. Mutant forms of ORF74 described in Figure 1 were cloned into a vector containing the hCD2 promoter and locus control region (LCR). (b) Northern blot analysis of thymic RNA from control and transgenic mice. Shown are representative samples from CDVG (line 19), L91D (lines 15 and 13), Δ22 (lines 7 and 58), and R2H (line 24) animals. Lower panel shows the ethidium bromide–stained RNA gels. (c) Histogram of ORF74 expression on thymic cells from control and CDVG (line 19) transgenic mice. Transgene expression is distinct and easily detectable at the cell surface by flow cytometry. (d) Relative number of thymocytes expressing ORF74, estimated by flow cytometry, in CDVG (lines 19 and 122), L91D (line 13), and R2H (line 24). Bars represent average ± SD (n = 3). p, progeny.