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B and Induces Proinflammatory Cytokine and Chemokine Production Via a C-Terminal Signaling Determinant
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Kaposi’s sarcoma-associated herpesvirus (KSHV) is believed to be
the causative agent of Kaposi’s sarcoma (KS), a multicentric growth
factor-dependent tumor common in AIDS patients characterized
histopathologically by spindle cell proliferation, angiogenesis, and
leukocyte infiltration. Recently, open reading frame 74 of KSHV has
been implicated as a major viral determinant of KS. Open reading frame
74 encodes KSHV G protein-coupled receptor (GPCR), a constitutively
active chemokine receptor that directly transforms NIH 3T3 cells in
vitro and induces multifocal KS-like lesions in KSHV-GPCR-transgenic
mice. Interestingly, receptor-positive cells are very rare in lesions
from these mice, implicating an indirect mechanism of tumorigenesis. In
this regard, here we report that expression of KSHV-GPCR in transfected
epithelial, monocytic, and T cell lines induced constitutive activation
of the immunoregulatory transcription factors AP-1 and NF-
B. This
was associated with constitutive induction of the proinflammatory
NF-B-dependent cytokines IL-1
, IL-6, and TNF-
, and chemokines
monocyte chemoattractant protein-1 and IL-8, as well as the
AP-1-dependent basic fibroblast growth factor. In addition, IL-2 and
IL-4 production was induced in transfected Jurkat T cells. Truncation
of the final five amino acids in the cytoplasmic tail of KSHV-GPCR
caused complete loss of its transforming and NF-B-inducing
activities, without affecting receptor expression or ligand binding.
These data suggest that KS results in part from KSHV-GPCR induction of
proinflammatory cytokine and growth factor gene expression, mediated by
a signaling determinant within the last five amino acids of the C
terminus, a domain that is also critical for direct cell
transformation.
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L. W. Shepard, M. Yang, P. Xie, D. D. Browning, T. Voyno-Yasenetskaya, T. Kozasa, and R. D. Ye Constitutive Activation of NF-kappa B and Secretion of Interleukin-8 Induced by the G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Involve Galpha 13 and RhoA J. Biol. Chem., November 30, 2001; 276(49): 45979 - 45987. [Abstract] [Full Text] [PDF]
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