title: Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity.
abstract: ONYX-015 is an adenovirus that lacks the E1B-55K gene product for p53 degradation. Thus, ONYX-015 was conceived as an oncolytic virus that would selectively replicate in p53-defective tumor cells. Here we show that loss of E1B-55K leads to the induction, but not the activation, of p53 in ONYX-015-infected primary cells. We use a novel adenovirus mutant, ONYX-053, to demonstrate that loss of E1B-55K-mediated late viral RNA export, rather than p53 degradation, restricts ONYX-015 replication in primary cells. In contrast, we show that tumor cells that support ONYX-015 replication provide the RNA export function of E1B-55K. These data reveal that tumor cells have altered mechanisms for RNA export and resolve the controversial role of p53 in governing ONYX-015 oncolytic selectivity.
authors.affiliation: UCSF Comprehensive Cancer Center, San Francisco, CA 94115, USA. coshea@cc.ucsf.edu
authors.forename: Clodagh C
authors.initials: CC
authors.lastname: O'Shea
authors.forename: Leisa
authors.initials: L
authors.lastname: Johnson
authors.forename: Bridget
authors.initials: B
authors.lastname: Bagus
authors.forename: Serah
authors.initials: S
authors.lastname: Choi
authors.forename: Cory
authors.initials: C
authors.lastname: Nicholas
authors.forename: Annie
authors.initials: A
authors.lastname: Shen
authors.forename: Larry
authors.initials: L
authors.lastname: Boyle
authors.forename: Kusum
authors.initials: K
authors.lastname: Pandey
authors.forename: Conrado
authors.initials: C
authors.lastname: Soria
authors.forename: John
authors.initials: J
authors.lastname: Kunich
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Shen
authors.forename: Gaston
authors.initials: G
authors.lastname: Habets
authors.forename: Dave
authors.initials: D
authors.lastname: Ginzinger
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D000260:Adenoviruses, Human / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D004279:DNA, Viral / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects / Q000821:virology; D015870:Gene Expression / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D034443:RNA Transport; D012367:RNA, Viral / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000378:metabolism; D014765:Viral Vaccines; D014779:Virus Replication / Q000235:genetics*; D051028:bcl-2-Associated X Protein
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; C493956:CDKN1A protein, human; D036022:Capsid Proteins; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004279:DNA, Viral; C477284:L4-100K protein, adenovirus type 5; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012367:RNA, Viral; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D014765:Viral Vaccines; D051028:bcl-2-Associated X Protein; C464532:dl1520; C018315:hexon capsid protein, Adenovirus; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases