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p53 DNA binding cooperativity is essential for apoptosis and tumor suppression in vivo

Oleg Timofeev1, Katharina Schlereth, Michael Wanzel

  • 1Department of Molecular Oncology, University of Marburg, 35032 Marburg, Germany.

Cell Reports
|May 14, 2013
PubMed

Insights

Tumor suppressor p53

Area of Science:

  • Molecular biology
  • Cancer research
  • Structural biology

Background:

  • The tumor suppressor p53 protein functions as a transcription factor that regulates genes involved in apoptosis, cell-cycle control, and DNA repair.
  • p53 functions as a tetramer, and its ability to bind DNA cooperatively is crucial for its tumor suppressor activity.
  • Mutations affecting p53's cooperative DNA binding have been identified in human cancers.

Purpose of the Study:

  • To investigate the functional consequences of mutations that disrupt p53's cooperative DNA binding.
  • To determine the role of p53 DNA binding cooperativity in tumor suppression and apoptosis.

Main Methods:

  • Analysis of p53E177R mutant mice, which harbor mutations compromising p53's cooperative DNA binding.
  • Assessment of various p53 functions, including apoptosis, cell-cycle control, senescence, metabolism, and antioxidant defense.
  • Evaluation of tumor development in p53E177R mutant mice under normal conditions and in response to oncogene induction.

Main Results:

  • p53-dependent apoptosis triggered by DNA damage and oncogenes was abolished in p53E177R mutant mice.
  • Cell-cycle control, senescence, metabolism, and antioxidant defense functions of p53 were retained in these mice.
  • Despite retained functions, p53E177R mutant mice were prone to developing spontaneous T cell lymphoma and other oncogene-induced tumors.

Conclusions:

  • p53 DNA binding cooperativity is essential for its apoptotic functions and plays a critical role in tumor suppression.
  • Mutations disrupting p53 cooperativity lead to a selective loss of apoptotic activity due to altered quaternary structure.
  • These findings highlight cooperativity mutations as a distinct class of p53 alterations relevant to cancer development.

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