title: Mutant mice lacking the p53 C-terminal domain model telomere syndromes.
abstract: Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53Δ31/Δ31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.
authors.affiliation: Genetics of Tumor Suppression, Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Iva
authors.initials: I
authors.lastname: Simeonova
authors.forename: Sara
authors.initials: S
authors.lastname: Jaber
authors.forename: Irena
authors.initials: I
authors.lastname: Draskovic
authors.forename: Boris
authors.initials: B
authors.lastname: Bardot
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.forename: Rachida
authors.initials: R
authors.lastname: Bouarich-Bourimi
authors.forename: Vincent
authors.initials: V
authors.lastname: Lejour
authors.forename: Laure
authors.initials: L
authors.lastname: Charbonnier
authors.forename: Claire
authors.initials: C
authors.lastname: Soudais
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bourdon
authors.forename: Michel
authors.initials: M
authors.lastname: Huerre
authors.forename: Arturo
authors.initials: A
authors.lastname: Londono-Vallejo
authors.forename: Franck
authors.initials: F
authors.lastname: Toledo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D017434:Protein Structure, Tertiary; D013577:Syndrome; D016615:Telomere / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53