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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics*
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Adenoviridae / metabolism
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Adenovirus E1A Proteins / genetics
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Adenovirus E1A Proteins / metabolism
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Adenovirus E1B Proteins / genetics
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Adenovirus E1B Proteins / metabolism
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Adenoviruses, Human / genetics
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Adenoviruses, Human / metabolism
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Apoptosis
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Blotting, Western
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Capsid Proteins / genetics
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Capsid Proteins / metabolism
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21
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Cytopathogenic Effect, Viral / genetics
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DNA, Viral / biosynthesis
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Epithelial Cells / metabolism
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Epithelial Cells / radiation effects
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Epithelial Cells / virology
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Gene Expression / genetics
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HCT116 Cells
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Humans
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In Situ Hybridization, Fluorescence
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Models, Biological
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Mutation
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / virology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Poly(ADP-ribose) Polymerases / metabolism
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Polymerase Chain Reaction
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Protein Biosynthesis / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-mdm2
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RNA Transport
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RNA, Viral / metabolism*
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Tumor Suppressor Protein p14ARF / metabolism
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Tumor Suppressor Protein p53 / metabolism*
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / metabolism
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Viral Plaque Assay
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Viral Proteins / metabolism
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Viral Vaccines
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Virus Replication / genetics*
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bcl-2-Associated X Protein
Substances
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Adenovirus E1A Proteins
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Adenovirus E1B Proteins
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CDKN1A protein, human
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Capsid Proteins
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Caspase Inhibitors
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DNA, Viral
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L4-100K protein, adenovirus type 5
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Viral
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Viral Nonstructural Proteins
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Viral Proteins
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Viral Vaccines
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bcl-2-Associated X Protein
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dl1520
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hexon capsid protein, Adenovirus
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Poly(ADP-ribose) Polymerases
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CASP3 protein, human
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Caspase 3
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Caspases