Epstein-Barr virus can inhibit genotoxin-induced G1 arrest downstream of p53 by preventing the inactivation of CDK2.
Epstein-Barr virus (EBV) is involved in the pathogenesis of several B cell lymphoproliferations, but the precise contribution it makes to the aetiology of each remains unclear. In vitro, the virus has potent growth transforming activity and efficiently induces the continuous proliferation of normal human B cells. A comparison of EBV-infected primary B cells with an isogenic population induced to proliferate by CD40-ligand (CD40L) and IL4 has revealed that EBV can override - by a novel mechanism - the p53/pRb-mediated G1 checkpoint activated in normal B cells by a genotoxic stress. In cells responding to cisplatin, although p53 is stabilized and activated, EBV latent gene expression appears to inhibit the accumulation of newly synthesized p21(WAF1/CIP1) and the downregulation of cyclin D2 that occur in the normal cells. Consequently, in the EBV-infected cells, CDK2 remains active, hyperphosphorylation of pRb is maintained and the replication of damaged DNA can occur. Under conditions of severe genomic stress, this absence of p21(WAF1/CIP1) function can result in apoptosis; however, when damage is less sustained, genomic instability may arise and this in turn could contribute to the development of a variety of EBV-associated B cell malignancies.
O'Nions
Jenny
J
Department of Virology and Ludwig Institute for Cancer Research, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK.
Allday
Martin J
MJ
D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D001973:Bromodeoxyuridine; D023201:CD40 Ligand / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects* / Q000502:physiology; D016158:Genes, p53 / Q000187:drug effects*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity*; D012260:Ribonucleases / Q000378:metabolism
D009153:Mutagens; D023201:CD40 Ligand; D015847:Interleukin-4; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D012260:Ribonucleases; D001973:Bromodeoxyuridine