Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase.
Werner syndrome is an autosomal recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases, including malignancy. To assess a potential collaboration between p21 or p53 cell cycle regulators and Wrn proteins, Wrn mutant mice were created and mated with p21 or p53 null mice to generate double mutants. The p21 null/Wrn mutant mice did not show an acceleration of tumorigenesis during the first year of life, suggesting that the p53-dependent G1-S cell cycle checkpoint (which operates via p21) is not involved in Wrn-abetted tumor suppression. In contrast, the p53 null/Wrn mutant mice were particularly remarkable with respect to the rapidity with which they developed tumors. These mice were also distinguished by the variety of tumors they developed compared to those that developed in p53 null mice. Such data suggest a genetic interaction between p53 and Wrn in which loss of Wrn provokes a more variable p53 response unrelated to its role in the G1-S cell cycle checkpoint.
Lebel
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Centre de Recherche en Cancérologie de l'Université Laval, Pavillon H tel-Dieu de Québec, Quebec, Canada.
Cardiff
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Leder
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D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004265:DNA Helicases / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics; D006394:Hemangiosarcoma / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics*; D017434:Protein Structure, Tertiary; D053484:RecQ Helicases; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D014898:Werner Syndrome / Q000150:complications / Q000201:enzymology / Q000235:genetics*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D053484:RecQ Helicases