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 an d 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 fi rst year of life, suggesting that the p53-dependent G(1)-S cell cycle check point (which operates via p21) is not involved in Wrn-abetted tumor suppres sion. In contrast, the p53 null/Wrn mutant mice were particularly remarkabl e with respect to the rapidity with which they developed tumors. These mice were also distinguished by the variety of tumors they developed compared t o those that developed in p53 null mice. Such data suggest a genetic intera ction between p53 and Wrn in which loss of Wrn provokes a more variable p53 response unrelated to its role in the G(1)-S cell cycle checkpoint.