p53 transactivation domain mutant knock-in mice provide novel insight into p53 tumor suppressor function.

摘要

The p53 tumor suppressor protein is critical to preventing the expansion of nascent tumor cells, as noted by the dramatic prevalence of p53 mutations in human cancers. To better define the molecular functions of p53 important for its role in tumor suppression, we generated and analyzed two strains of p53 knock-in mice, in which mutant forms of p53 were introduced into the endogenous p53 genomic locus. The analysis of these mutant mice, one which is hypomorphic as a transactivator and one which is hypermorphic as a transactivator, has provided novel insight into p53 function at both the molecular and cellular level. Our data demonstrate that p53 utilizes distinct pathways to induce apoptosis in response to specific stresses, with the role of robust transcriptional activation by p53 critical for the response to acute genotoxic stress, but not hypoxia. We have also shown that the cellular response by p53 to a chronic, low-dose DNA damage stress utilizes a distinct pathway than that involved in the response to single, high-dose of genotoxic stress, with robust transactivation of p53 target genes being crucial for the latter, but not the former. We further demonstrated that p19Arf is critical for the cellular response to chronic genotoxic stress, but is completely dispensable for the response to a single, high-dose of DNA damage; intriguingly, our data also suggest that pl9Arf may be acting in a manner independent of p53 activation in the context of a chronic genotoxic stress response. We also demonstrate that the ability of p53 to suppress tumor formation is not strictly dependent on its ability to robustly transactivate a wide range of its target genes. These studies have revealed novel mechanisms through which p53 acts, and provide great insight into how the cellular machinery works to prevent cancer.