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

TY - JOUR

T1 - Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

AU - Holst, P J

AU - Rosenkilde, M M

AU - Manfra, D

AU - Chen, S C

AU - Wiekowski, M T

AU - Holst, B

AU - Cifire, F

AU - Lipp, M

AU - Schwartz, T W

AU - Lira, S A

N1 - 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

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

U2 - 10.1172/JCI13622

DO - 10.1172/JCI13622

M3 - Journal article

C2 - 11748262

SN - 0021-9738

VL - 108

SP - 1789

EP - 1796

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

ER -