Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes
| Autor: | Sara Jaber, Ming Fang, Michel Huerre, Boris Bardot, Laure Charbonnier, Claire Soudais, Franck Toledo, Rachida Bouarich-Bourimi, Jean-Christophe Bourdon, Iva Simeonova, Irena Draskovic, Vincent Lejour, Arturo Londoño-Vallejo |
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| Přispěvatelé: | Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CD4+T-Lymphocytes and Anti-Tumour Response, University of Dundee, Département de Pathologie [Curie], Institut Curie [Paris], HAL UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Dynamique de l'information génétique : bases fondamentales et cancer ( DIG CANCER ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Telomeres and Cancer Laboratory, INSTITUT CURIE, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Institut Curie |
| Rok vydání: | 2013 |
| Předmět: |
Male
Telomere-Binding Proteins Mutant Gene Expression [SDV.CAN]Life Sciences [q-bio]/Cancer Biology TINF2 medicine.disease_cause General Biochemistry Genetics and Molecular Biology Dyskerin [ SDV.CAN ] Life Sciences [q-bio]/Cancer Mice 03 medical and health sciences 0302 clinical medicine [SDV.CAN] Life Sciences [q-bio]/Cancer [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Pulmonary fibrosis medicine Animals Humans Aplastic anemia lcsh:QH301-705.5 030304 developmental biology 0303 health sciences Mutation Syndrome Telomere medicine.disease Mice Mutant Strains Protein Structure Tertiary 3. Good health Disease Models Animal lcsh:Biology (General) [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] 030220 oncology & carcinogenesis Cancer research [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Tumor Suppressor Protein p53 Dyskeratosis congenita |
| Zdroj: | Cell Reports Cell Reports, Elsevier Inc, 2013, 3 (6), pp.2046-2058. ⟨10.1016/j.celrep.2013.05.028⟩ Cell Reports, 2013, 3 (6), pp.2046-2058. ⟨10.1016/j.celrep.2013.05.028⟩ Cell Reports, Elsevier Inc, 2013, 3 (6), pp.2046-2058. 〈10.1016/j.celrep.2013.05.028〉 Cell Reports, Vol 3, Iss 6, Pp 2046-2058 (2013) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2013.05.028 |
| Popis: | International audience; Mutations in p53, although frequent in human cancers , have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53 D31 , 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, p53 D31/D31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Hetero-zygous p53 +/D31 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 p53 D31/D31 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. |
| Databáze: | OpenAIRE |
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