title: Epstein-Barr virus latent membrane protein 2A contributes to anoikis resistance through ERK activation.
abstract: Epstein-Barr virus (EBV) is associated with various malignancies, including epithelial cancers. In this study, we analyzed the effect of EBV infection on epithelial cells by using EBV-converted epithelial cells. In EBV-positive cells, the extracellular signal-regulated kinase (ERK) pathway is constitutively activated. Inhibition of ERK activity leads to reduced anoikis resistance; therefore, EBV-positive cells are more resistant to anoikis, a type of apoptosis induced by cell detachment, than are EBV-negative cells. Among the viral genes expressed in EBV-positive cells, the latent membrane protein 2A (LMP2A) is responsible for induction of ERK-mediated anoikis resistance, although the expression level of LMP2A is much lower in EBV-positive cells than in EBV-transformed B cells. Further analysis demonstrated that LMP2A downregulation of the proanoikis mediator Bim through proteasomal degradation is dependent on the immunoreceptor tyrosine-based activation motif (ITAM). These findings suggest that LMP2A-mediated ERK activation is involved in the generation of EBV-associated epithelial malignancies.
authors.affiliation: Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. iwakiri@igm.hokudai.ac.jp
authors.forename: Dai
authors.initials: D
authors.lastname: Iwakiri
authors.forename: Takeharu
authors.initials: T
authors.lastname: Minamitani
authors.forename: Mrinal
authors.initials: M
authors.lastname: Samanta
mesh_terms: D023102:Anoikis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D061625:Immunoreceptor Tyrosine-Based Activation Motif / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D017931:DNA Primers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014763:Viral Matrix Proteins