Deconstructing p53 Transcriptional Networks in Tumor Suppression

The p53 transcription factor is mutated in at least half of all human cancers, including hematological malignancies, and p53-deficient mice develop cancer, primarily lymphomas, at 100% frequency, together underscoring the critical role for p53 in tumor suppression. Although p53 can restrain neoplastic cell expansion by inducing cell-cycle arrest or apoptosis in response to diverse stress signals, the molecular pathways through which p53 acts in tumor suppression remain largely elusive. To define the transcriptional programs underlying p53 tumor suppressor function, we have used mouse genetic and genomic approaches. We generated a set of p53 knock-in mouse strains expressing mutants in the first (p53^25,26), second (p53^53,54), or both (p53^25,26,53,54) of two transcriptional activation domains (TADs). We found that p53^25,26 is severely compromised for transactivation of most classical p53 target genes, but retains the ability to activate a subset of p53 target genes, while p53^53,54  is uncompromised in transcriptional activity and p53^25,26,53,54 lacks transactivation activity completely. Interestingly, although unable to trigger apoptosis or cell-cycle arrest in response to acute DNA damage signals, p53^25,26 retains full activity in suppressing various cancer types, indicating that efficient transactivation of most canonical p53 targets is dispensable for tumor suppression. In contrast, p53^25,26,53,54 is completely inactive in tumor suppression, highlighting the importance of transactivation function for tumor suppression. Importantly, as p53^25,26 activates only a subset of p53-dependent genes, yet retains tumor suppressor activity, it has helped to pinpoint a small group of novel direct p53-inducible tumor suppression-associated genes, whose functions we are currently analyzing in depth using genetic and cell biological techniques. These approaches will help better define the transcriptional networks important for p53 function in tumor suppression, which will ultimately facilitate the design of novel therapies for the many cancers in which p53 is inactivated.