title: Tumorigenesis and aberrant signaling in transgenic mice expressing the human herpesvirus-8 K1 gene.
abstract: BACKGROUND
  The K1 gene of human herpesvirus-8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus) encodes a transmembrane signaling protein that elicits cellular activation events. To evaluate the potential role of K1 in HHV-8-associated pathogenesis, we produced transgenic mice expressing the HHV-8 K1 gene under the transcriptional control of the simian virus 40 promoter.
  
  
  METHODS
  Three independent heterozygous transgenic K1 mouse lines were generated from founder mice. Mouse splenic and thymic lymphocytes and tumor tissues were analyzed for the expression of cytokines involved in inflammatory and immune responses, including tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and interleukin 12 (IL-12); for the activation of the transcription factors nuclear factor-kappaB (NF-kappaB) and the B cell-specific transcription factor Oct-2; and for the activation of the Src and Syk family kinases, components of B-cell receptor-induced signal-transduction pathways.
  
  
  RESULTS
  Expression of bFGF was increased in K1-transgenic mice as compared with nontransgenic mice, whereas expression of TNF-alpha and IL-6 did not differ using reverse transcriptase-polymerase chain reaction. K1-transgenic mice showed substantially less serum IL-12 induction than did nontransgenic mice when challenged with a lipopolysaccharide. B lymphocytes from K1-transgenic mice but not from nontransgenic mice showed constitutive activation of NF-kappaB and Oct-2. K1 expression in human B lymphocytes stimulated NF-kappaB-dependent promoter activity. B lymphocytes from K1-transgenic mice also showed increased phosphorylation of Lyn, a Src family tyrosine kinase, and enhanced Lyn activity. Tumors in K1-transgenic mice showed features indicative of a spindle-cell sarcomatoid tumor and a malignant plasmablastic lymphoma. The pattern of cytokine, transcription factor, and Lyn kinase activity in the lymphoma was similar to that in B lymphocytes from K1-transgenic mice.
  
  
  CONCLUSIONS
  K1 may be involved in the activation of NF-kappaB signaling. The enhanced NF-kappaB activity in nonmalignant lymphocytes of K1 mice and its persistence in lymphoma tumors of these mice suggest that the K1 mouse may be a model of premalignancy.
authors.affiliation: Laboratory of Molecular Oncology, Ochsner Clinic Foundation, New Orleans, LA 70121, USA. oprakash@ochsner.org
authors.forename: Om
authors.initials: O
authors.lastname: Prakash
authors.forename: Zhen-Ya
authors.initials: ZY
authors.lastname: Tang
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Peng
authors.forename: Roy
authors.initials: R
authors.lastname: Coleman
authors.forename: Javed
authors.initials: J
authors.lastname: Gill
authors.forename: Gist
authors.initials: G
authors.lastname: Farr
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers; D004789:Enzyme Activation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006566:Herpesviridae Infections / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; D017931:DNA Primers; D006023:Glycoproteins; C111600:K1 protein, Human herpesvirus 8; D012333:RNA, Messenger; D014764:Viral Proteins; D018664:Interleukin-12; D011505:Protein-Tyrosine Kinases