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

Thomas M Johnson1, Kristin Meade, Navneeta Pathak

  • 1Departments of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 25, 2008
PubMed

Insights

The tumor suppressor p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The tumor suppressor protein p53 regulates diverse cellular processes, including apoptosis and senescence.
  • p53's transactivation-dependent and -independent functions are difficult to dissociate due to overlapping motifs.
  • The precise contribution of transcriptional activation to p53's tumor suppressor role is unclear.

Purpose of the Study:

  • To determine the relative contribution of p53's transactivation-dependent and -independent functions to its effector roles.
  • To investigate the role of p53 transactivation in apoptosis and cellular senescence.

Main Methods:

  • Generated knockin mice expressing a p53 mutant (p53(VP16)) with transactivation-independent domains removed but retaining transactivation ability via fusion to the VP16 domain.
  • Assessed the ability of p53(VP16) to activate p53 target genes involved in apoptosis and senescence.
  • Evaluated p53(VP16) function in mouse fibroblasts under various conditions.

Main Results:

  • The p53(VP16) mutant robustly activated transcription of p53 targets for apoptosis and senescence.
  • p53(VP16) selectively triggered senescence but not apoptosis in mouse fibroblasts, despite being transactivation-competent.
  • This indicates a dissociation between p53's ability to induce senescence and apoptosis.

Conclusions:

  • p53 transactivation is central to inducing cellular senescence.
  • p53 transactivation alone is insufficient to trigger apoptosis.
  • This research provides insights into the mechanisms of p53-mediated tumor suppression.

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