title: Down-regulation of the TGF-beta target gene, PTPRK, by the Epstein-Barr virus encoded EBNA1 contributes to the growth and survival of Hodgkin lymphoma cells.
abstract: The Epstein-Barr virus (EBV) contributes to the growth and survival of Hodgkin lymphoma (HL) cells. Here we report that down-regulation of the transforming growth factor-beta (TGF-beta) target gene, protein tyrosine phosphatase receptor kappa (PTPRK), followed EBV infection of HL cells and was also more frequently observed in the Hodgkin and Reed-Sternberg (HRS) cells of EBV-positive compared with EBV-negative primary HL. The viability and proliferation of EBV-positive HL cells was decreased by overexpression of PTPRK, but increased following the knockdown of PTPRK expression in EBV-negative HL cells, demonstrating that PTPRK is a functional tumor suppressor in HL. EBV suppressed the TGF-beta-mediated activation of PTPRK expression, suggesting disruption of TGF-beta signaling upstream of PTPRK. This was confirmed when we showed that the Epstein-Barr nuclear antigen-1 (EBNA1) decreased Smad2 protein levels and that this was responsible for PTPRK down-regulation. EBNA1 decreased the half-life of Smad2 but did not interact with Smad2. By down-regulating Smad2 protein expression, EBNA1 apparently disables TGF-beta signaling, which subsequently decreases transcription of the PTPRK tumor suppressor. We speculate that loss of the phosphatase function of PTPRK may activate as-yet-unidentified growth-promoting protein tyrosine kinases, which in turn contribute to the pathogenesis of EBV-positive HL.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, The Medical School, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, United Kingdom.
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Flavell
authors.forename: Karl R N
authors.initials: KR
authors.lastname: Baumforth
authors.forename: Victoria H J
authors.initials: VH
authors.lastname: Wood
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Davies
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: Susan
authors.initials: S
authors.lastname: Morgan
authors.forename: Andrew
authors.initials: A
authors.lastname: Boyce
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Kelly
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
mesh_terms: D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D016147:Genes, Tumor Suppressor / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D006801:Humans; D008297:Male; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C489852:PTPRK protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; C417029:EBV-encoded nuclear antigen 1