title: Activation of Src kinase Lyn by the Kaposi sarcoma-associated herpesvirus K1 protein: implications for lymphomagenesis.
abstract: The K1 gene of Kaposi sarcoma-associated herpesvirus (KSHV) encodes a transmembrane glycoprotein bearing a functional immunoreceptor tyrosine-based activation motif (ITAM). Previously, we reported that the K1 protein induced plasmablastic lymphomas in K1 transgenic mice, and that these lymphomas showed enhanced Lyn kinase activity. Here, we report that systemic administration of the nuclear factor kappa B (NF-kappaB) inhibitor Bay 11-7085 or an anti-vascular endothelial growth factor (VEGF) antibody significantly reduced K1 lymphoma growth in nude mice. Furthermore, in KVL-1 cells, a cell line derived from a K1 lymphoma, inhibition of Lyn kinase activity by the Src kinase inhibitor PP2 decreased VEGF induction, NF-kappaB activity, and the cell proliferation index by 50% to 75%. In contrast, human B-cell lymphoma BJAB cells expressing K1, but not the ITAM sequence-deleted mutant K1, showed a marked increase in Lyn kinase activity with concomitant VEGF induction and NF-kappaB activation, indicating that ITAM sequences were required for the Lyn kinase-mediated activation of these factors. Our results suggested that K1-mediated constitutive Lyn kinase activation in K1 lymphoma cells is crucial for the production of VEGF and NF-kappaB activation, both strongly implicated in the development of KSHV-induced lymphoproliferative disorders.
authors.affiliation: Laboratory of Molecular Oncology, Ochsner Clinic Foundation, 1516 Jefferson Highway, New Orleans, LA 70121, USA. oprakash@ochsner.org
authors.forename: Om
authors.initials: O
authors.lastname: Prakash
authors.forename: O Rama
authors.initials: OR
authors.lastname: Swamy
authors.forename: Xiochang
authors.initials: X
authors.lastname: Peng
authors.forename: Zhen-Ya
authors.initials: ZY
authors.lastname: Tang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Janet E
authors.initials: JE
authors.lastname: Larson
authors.forename: J Craig
authors.initials: JC
authors.lastname: Cohen
authors.forename: Javed
authors.initials: J
authors.lastname: Gill
authors.forename: Gist
authors.initials: G
authors.lastname: Farr
authors.forename: Suizhao
authors.initials: S
authors.lastname: Wang
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D019288:Herpesvirus 8, Human; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000906:Antibodies; C111600:K1 protein, Human herpesvirus 8; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases