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The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a gamma-2 herpesvirus [1-5] that is implicated in the pathogenesis of Kaposi's sarcoma [1-5] and of primary effusion B-cell lymphomas (PELs) [6]. KSHV infects malignant and progenitor cells of Kaposi's sarcoma [7] and PEL [2,6,8], it encodes putative oncogenes [4,5,9] and genes that may cause Kaposi's sarcoma pathogenesis by stimulating angiogenesis [4,5,9,10]. The G-protein-coupled receptor encoded by an open reading frame (ORF 74) of KSHV [9] is expressed in Kaposi's sarcoma lesions and in PEL [9,11] and stimulates signalling pathways linked to cell proliferation [12] in a constitutive (agonist-independent) way [12]. Here we show that signalling by this KSHV G-protein-coupled receptor leads to cell transformation and tumor-igenicity, and induces a switch to an angiogenic phenotype [13] mediated by vascular endothelial growth factor [14], an angiogenesis [13,14] and Kaposi's-spindle-cell growth factor [15-17]. We find that this receptor can activate two protein kinases, JNK/SAPK and p38MAPK, by triggering signalling cascades like those induced by inflammatory cytokines [18] that are angiogenesis activators [19] and mitogens for Kaposi's sarcoma cells [10] and B cells. We conclude that the KSHV G-protein-coupled receptor is a viral oncogene that can exploit cell signalling pathways to induce transformation and angiogenesis in KSHV-mediated oncogenesis.

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