title: Inhibition of latent membrane protein 1 impairs the growth and tumorigenesis of latency II Epstein-Barr virus-transformed T cells.
abstract: Epstein-Barr virus (EBV) is a common human herpesvirus. Infection with EBV is associated with several human malignancies in which the virus expresses a set of latent proteins, among which is latent membrane protein 1 (LMP1). LMP1 is able to transform numerous cell types and is considered the main oncogenic protein of EBV. The mechanism of action is based on mimicry of activated members of the tumor necrosis factor (TNF) receptor superfamily, through the ability of LMP1 to bind similar adapters and to activate signaling pathways. We previously generated two unique models: a monocytic cell line and a lymphocytic (NC5) cell line immortalized by EBV that expresses the type II latency program. Here we generated LMP1 dominant negative forms (DNs), based on fusion between green fluorescent protein (GFP) and transformation effector site 1 (TES1) or TES2 of LMP1. Then we generated cell lines conditionally expressing these DNs. These DNs inhibit NF-κB and Akt pathways, resulting in the impairment of survival processes and increased apoptosis in these cell lines. This proapoptotic effect is due to reduced interaction of LMP1 with specific adapters and the recruitment of these adapters to DNs, which enable the generation of an apoptotic complex involving TRADD, FADD, and caspase 8. Similar results were obtained with cell lines displaying a latency III program in which LMP1-DNs decrease cell viability. Finally, we prove that synthetic peptides display similar inhibitory effects in EBV-infected cells. DNs derived from LMP1 could be used to develop therapeutic approaches for malignant diseases associated with EBV.
authors.affiliation: CNRS UMR8161, Institut de Biologie de Lille, IFR 142, Université Lille-Nord de France, Lille, France. eric.adriaenssens@ibl.fr
authors.forename: Papa Alioune
authors.initials: PA
authors.lastname: Ndour
authors.forename: Guillaume
authors.initials: G
authors.lastname: Brocqueville
authors.forename: Tan-Sothéa
authors.initials: TS
authors.lastname: Ouk
authors.forename: Gautier
authors.initials: G
authors.lastname: Goormachtigh
authors.forename: Olivier
authors.initials: O
authors.lastname: Morales
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mougel
authors.forename: Julie
authors.initials: J
authors.lastname: Bertout
authors.forename: Oleg
authors.initials: O
authors.lastname: Melnyk
authors.forename: Véronique
authors.initials: V
authors.lastname: Fafeur
authors.forename: Jean
authors.initials: J
authors.lastname: Feuillard
authors.forename: Jean
authors.initials: J
authors.lastname: Coll
authors.forename: Eric
authors.initials: E
authors.lastname: Adriaenssens
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D002472:Cell Transformation, Viral; D015536:Down-Regulation; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins