title: Dominant effects of Δ40p53 on p53 function and melanoma cell fate.
abstract: The TP53 gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of TP53 mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulating TP53 activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first 40 N-terminal amino acids of the full-length protein including the transactivation and Mdm2-binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased the levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear heterotetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain and cyclin-dependent kinase inhibitor, p21. Δ40p53 altered the promoter occupancy of these downstream p53 target genes in such a way that it shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53.
authors.affiliation: Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota, USA; Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Rie
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Internal Medicine/Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA; Oncology/Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA; Immunology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: Markovic.Svetomir@mayo.edu.
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.affiliation: Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA; Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA; Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Scrable
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001932:Brain Neoplasms; D059447:Cell Cycle Checkpoints / Q000502:physiology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma; D006801:Humans; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053418:Death Domain Receptor Signaling Adaptor Proteins; C485896:PIDD1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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