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The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells

Oncogene volume 23, pages 514–523 (2004)Cite this article

Abstract

Kaposi's sarcoma-associated virus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The KSHV G protein-couple receptor (vGPCR) is a homologue of the human IL-8 receptor that signals constitutively, activates mitogen- and stress-activated kinases, and induces transcription via multiple transcription factors including AP-1 and NFκB. Furthermore, vGPCR causes cellular transformation in vitro and leads to KS-like tumors in transgenic mouse models. vGPCR has therefore become an exciting potential therapeutic target for KSHV-mediated disease, but its signaling properties need to be better understood in the context of KSHV-infected hematopoietic cells. We recently described a PEL cell line that expresses vGPCR via an inducible promoter and have shown that vGPCR has broad capabilities of affecting cellular and viral transcription patterns in this highly relevant cell type. To elucidate the predominant signaling pathways used by vGPCR in PEL cells, we have used reporter gene assays to measure vGPCR activity in the presence of various pharmacologic enzyme inhibitors and plasmid constructs. We show that vGPCR-induced activation of AP-1 and CREB is mediated cooperatively by a Gq-ERK-1/2 and a Gi–PI3K-Src axis. Furthermore, unlike in other cell types, NFκB activation by vGPCR seems not to be substantially mediated by Gi or PI3K/Akt in PEL cells.

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Acknowledgements

We thank Elizabeth Geras-Raaka, Marvin Gershengorn, and Xin-Yun Huang for all their sound advice and helpful reagents. We also thank Dominique Brandt for technical advice on Src kinase assays. Part of this work was carried out when MC was a fellow of the Lymphoma Research Foundation of America. This work was supported by NIH Grants K08-AI53971-01 to MC, and R01-CA73531 to EC.

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  1. Division of International Medicine and Infectious Disease, Department of Medicine, Weill Medical College of Cornell University, 1300 York Ave., Room A-421, New York, 10021, NY, USA

    Mark L Cannon

  2. Department of Pathology, Weill Medical College of Cornell University, 1300 York Ave., Room C-410, New York, 10021, NY, USA

    Ethels Cesarman

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Correspondence to Mark L Cannon.

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Cannon, M., Cesarman, E. The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells. Oncogene 23, 514–523 (2004). https://doi.org/10.1038/sj.onc.1207021

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