title: Δ122p53, a mouse model of Δ133p53α, enhances the tumor-suppressor activities of an attenuated p53 mutant.
abstract: Growing evidence suggests the Δ133p53α isoform may function as an oncogene. It is overexpressed in many tumors, stimulates pathways involved in tumor progression, and inhibits some activities of wild-type p53, including transactivation and apoptosis. We hypothesized that Δ133p53α would have an even more profound effect on p53 variants with weaker tumor-suppressor capability. We tested this using a mouse model heterozygous for a Δ133p53α-like isoform (Δ122p53) and a p53 mutant with weak tumor-suppressor function (mΔpro). The Δ122p53/mΔpro mice showed a unique survival curve with a wide range of survival times (92-495 days) which was much greater than mΔpro/- mice (range 120-250 days) and mice heterozygous for the Δ122p53 and p53 null alleles (Δ122p53/-, range 78-150 days), suggesting Δ122p53 increased the tumor-suppressor activity of mΔpro. Moreover, some of the mice that survived longest only developed benign tumors. In vitro analyses to investigate why some Δ122p53/mΔpro mice were protected from aggressive tumors revealed that Δ122p53 stabilized mΔpro and prolonged the response to DNA damage. Similar effects of Δ122p53 and Δ133p53α were observed on wild-type of full-length p53, but these did not result in improved biological responses. The data suggest that Δ122p53 (and Δ133p53α) could offer some protection against tumors by enhancing the p53 response to stress.
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: T L
authors.initials: TL
authors.lastname: Slatter
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: N
authors.initials: N
authors.lastname: Hung
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: S
authors.initials: S
authors.lastname: Bowie
authors.affiliation: Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Campbell
authors.affiliation: Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Rubio
authors.affiliation: Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Speidel
authors.affiliation: Department of Microbiology and Immunology, School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: M
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: M
authors.initials: M
authors.lastname: Baird
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: J A
authors.initials: JA
authors.lastname: Royds
authors.affiliation: 1] Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand [2] Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia [3] Maurice Wilkins Centre for BioDiscovery, University of Otago, Dunedin, New Zealand.
authors.forename: A W
authors.initials: AW
authors.lastname: Braithwaite
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage / Q000235:genetics*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007976:Leupeptins / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015853:Cysteine Proteinase Inhibitors; D015850:Interleukin-6; D007976:Leupeptins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde