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Knockin mice expressing a chimeric p53 protein reveal mechanistic differences in how p53 triggers apoptosis and senescence

Johnson, Thomas M., Meade, Kristin, Pathak, Navneeta, Marques, Michelle R., Attardi, Laura D.
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.4 pp. 1215-1220
DNA replication, apoptosis, cell senescence, centrosomes, chimerism, fibroblasts, herpes simplex, homologous recombination, mice, mutants, recombinant fusion proteins, transcription (genetics), transcriptional activation, viruses
The contribution of transcriptional activation to the p53 effector functions critical for tumor suppression, apoptosis and cellular senescence, remains unclear because of p53's ability to regulate diverse cellular processes in a transactivation-independent manner. Dissociating the importance of transactivation from other p53 functions, including regulating transcriptional repression, DNA replication, homologous recombination, centrosome duplication, and mitochondrial function, has been difficult because of overlapping motifs for these functions in the amino terminus. To determine the relative contribution of these activities and transactivation to p53 function, we generated knockin mice expressing a p53 mutant lacking domains involved in these transactivation-independent functions, while remaining competent for transactivation through fusion to the Herpes Simplex Virus VP16 transactivation domain. This chimeric mutant, termed p53VP¹⁶, robustly activates the transcription of a range of p53 targets involved in both apoptosis and senescence. Intriguingly, despite being transactivation-competent, this chimeric protein shows selectivity in p53 effector function in mouse fibroblasts, with a capacity to trigger senescence but not apoptosis under a variety of conditions. Our study highlights the central role of p53 transactivation for senescence while suggesting that transactivation is insufficient for apoptosis, and provides insight into the mechanisms by which p53 serves as a tumor suppressor.