4.8 Article

p53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo

Journal

CELL REPORTS
Volume 3, Issue 5, Pages 1512-1525

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2013.04.008

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Funding

  1. DFG [TR17, TR81, KFO 210]
  2. European Research Council
  3. Deutsche Krebshilfe
  4. Von Behring-Rontgen-Stiftung
  5. Deutsche Jose Carreras Leukamie Stiftung
  6. Universities of Giessen and Marburg Lung Center (LOEWE)

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Four molecules of the tumor suppressor p53 assemble to cooperatively bind proapoptotic target genes. The structural basis for cooperativity consists of interactions between adjacent DNA binding domains. Mutations at the interaction interface that compromise cooperativity were identified in cancer patients, suggesting a requirement of cooperativity for tumor suppression. We report on an analysis of cooperativity mutant p53(E177R) mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereas functions in cell-cycle control, senescence, metabolism, and antioxidant defense were retained and were sufficient to suppress development of spontaneous T cell lymphoma. Cooperativity mutant mice are nevertheless highly cancer prone and susceptible to different oncogene-induced tumors. Our data underscore the relevance of DNA binding cooperativity for p53-dependent apoptosis and tumor suppression and highlight cooperativity mutations as a class of p53 mutations that result in a selective loss of apoptotic functions due to an altered quaternary structure of the p53 tetramer.

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