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

Published

Journal Article

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 p53(VP16), 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.

Full Text

Duke Authors

Cited Authors

  • Johnson, TM; Meade, K; Pathak, N; Marques, MR; Attardi, LD

Published Date

  • January 29, 2008

Published In

Volume / Issue

  • 105 / 4

Start / End Page

  • 1215 - 1220

PubMed ID

  • 18216268

Pubmed Central ID

  • 18216268

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.0706764105

Language

  • eng

Conference Location

  • United States