title: Inhibition of p53 expression by peptide-conjugated phosphorodiamidate morpholino oligomers sensitizes human cancer cells to chemotherapeutic drugs.
abstract: The p53 tumor suppressor gene encodes a transcription factor that is commonly mutated in cancer. Tumors arise when premalignant cells are unable to undergo p53-dependent apoptosis, cell cycle arrest or DNA repair. The p53-signaling pathway affects not only tumor development, but also the response of tumors to chemotherapeutic drugs. In this study, we use cell penetrating peptide conjugates of phosphorodiamidate morpholino oligomers (PPMOs) to inhibit p53 expression. We examine the functional properties of endogenous p53 isoforms that are produced upon PPMO-mediated inhibition of p53 translation and splicing, and report that loss of N-terminal or C-terminal sequences interferes with the transcriptional activity of p53. Importantly, we report that PPMO-mediated inhibition of p53 expression sensitizes human cancer cells with wild-type p53 to chemotherapeutic drugs.
authors.affiliation: Department of Biology, York University, 4700 Keele St., Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Ma
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: W
authors.initials: W
authors.lastname: Xuan
authors.forename: P L
authors.initials: PL
authors.lastname: Iversen
authors.forename: L J
authors.initials: LJ
authors.lastname: Smith
authors.forename: S
authors.initials: S
authors.lastname: Benchimol
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D060172:Morpholinos / Q000494:pharmacology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012326:RNA Splicing / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004337:Drug Carriers; D060172:Morpholinos; D050505:Mutant Proteins; D020033:Protein Isoforms; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin