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Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression

Academic Article
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Overview

authors

  • Chao, C.
  • Herr, D.
  • Chun, Jerold
  • Xu, Y.

publication date

  • June 2006

journal

  • EMBO Journal  Journal

abstract

  • Mouse p53 is phosphorylated at Ser18 and Ser23 after DNA damage. To determine whether these two phosphorylation events have synergistic functions in activating p53 responses, we simultaneously introduced Ser18/23 to Ala mutations into the endogenous p53 locus in mice. While partial defects in apoptosis are observed in p53S18A and p53S23A thymocytes exposed to IR, p53-dependent apoptosis is essentially abolished in p53S18/23A thymocytes, indicating that these two events have critical and synergistic roles in activating p53-dependent apoptosis. In addition, p53S18/23A, but not p53S18A, could completely rescue embryonic lethality of Xrcc4(-/-) mice that is caused by massive p53-dependent neuronal apoptosis. However, certain p53-dependent functions, including G1/S checkpoint and cellular senescence, are partially retained in p53(S18/23A) cells. While p53(S18A) mice are not cancer prone, p53S18/23A mice developed a spectrum of malignancies distinct from p53S23A and p53(-/-) mice. Interestingly, Xrcc4(-/-)p53S18/23A mice fail to develop tumors like the pro-B cell lymphomas uniformly developed in Xrcc4(-/-) p53(-/-) animals, but exhibit developmental defects typical of accelerated ageing. Therefore, Ser18 and Ser23 phosphorylation is important for p53-dependent suppression of tumorigenesis in certain physiological context.

subject areas

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Cells, Cultured
  • DNA Damage
  • DNA-Binding Proteins
  • Embryo, Mammalian
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Neoplasms
  • Phosphorylation
  • Serine
  • Survival Rate
  • Thymus Gland
  • Tumor Suppressor Protein p53
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Research

keywords

  • apoptosis
  • gene expression
  • phosphorylation
  • tumor suppression
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Identity

PubMed Central ID

  • PMC1478190

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/sj.emboj.7601167

PubMed ID

  • 16757976
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Additional Document Info

start page

  • 2615

end page

  • 2622

volume

  • 25

issue

  • 11

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