Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity
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Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity. / Holst, P J; Rosenkilde, M M; Manfra, D; Chen, S C; Wiekowski, M T; Holst, B; Cifire, F; Lipp, M; Schwartz, T W; Lira, S A.
I: Journal of Clinical Investigation, Bind 108, Nr. 12, 2001, s. 1789-96.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 108
SP - 1789
EP - 1796
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -
ID: 10536519