The KSHV G Protein-Coupled Receptor Signals via Multiple Pathways to Induce Transcription Factor Activation in Primary Effusion Lymphoma Cells

Oncogene. 2004 Jan 15;23(2):514-23. doi: 10.1038/sj.onc.1207021.

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 NFkappaB. 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, NFkappaB activation by vGPCR seems not to be substantially mediated by Gi or PI3K/Akt in PEL cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Herpesvirus 8, Human*
  • Humans
  • Lymphoma / enzymology
  • Lymphoma / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, Chemokine / metabolism*
  • Signal Transduction*
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Viral Proteins / metabolism*
  • src-Family Kinases / metabolism

Substances

  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • G protein-coupled receptor, Human herpesvirus 8
  • NF-kappa B
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Receptors, Chemokine
  • Transcription Factor AP-1
  • Transcription Factors
  • Viral Proteins
  • Phosphatidylinositol 3-Kinases
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gq-G11