Analysis of ku80-mutant mice and cells with deficient levels of p53

Dae Sik Lim, Hannes Vogel, Dennis M. Willerford, Arthur T. Sands, Kenneth A. Platt, Edward P Hasty

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Absence of Ku80 results in increased sensitivity to ionizing radiation, defective lymphocyte development, early onset of an age-related phenotype, and premature replicative senescence. Here we investigate the role of p53 on the phenotype of ku80-mutant mice and cells. Reducing levels of p53 increased the cancer incidence for ku80(-/-) mice. About 20% of ku80(-/-) p53(+/-) mice developed a broad spectrum of cancer by 40 weeks and all ku80(-/-) p53(-/-) mice developed pro-B-cell lymphoma by 16 weeks. Reducing levels of p53 rescued populations of ku80(-/-) cells from replicative senescence by enabling spontaneous immortalization. The double-mutant cells are impaired for the G1/S checkpoint due to the p53 mutation and are hypersensitive to χ-radiation and reactive oxygen species due to the Ku80 mutation. These data show that replicative senescence is caused by a p53-dependent cell cycle response to damaged DNA in ku80(-/-) cells and that p53 is essential for preventing very early onset of pro-B-cell lymphoma in ku80(-/-) mice.

Original languageEnglish (US)
Pages (from-to)3772-3780
Number of pages9
JournalMolecular and Cellular Biology
Volume20
Issue number11
DOIs
StatePublished - Jun 2000
Externally publishedYes

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Cell Aging
B-Lymphoid Precursor Cells
B-Cell Lymphoma
Phenotype
Mutation
Ionizing Radiation
Age of Onset
Reactive Oxygen Species
Neoplasms
Cell Cycle
Lymphocytes
Radiation
DNA
Incidence
Population

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Analysis of ku80-mutant mice and cells with deficient levels of p53. / Lim, Dae Sik; Vogel, Hannes; Willerford, Dennis M.; Sands, Arthur T.; Platt, Kenneth A.; Hasty, Edward P.

In: Molecular and Cellular Biology, Vol. 20, No. 11, 06.2000, p. 3772-3780.

Research output: Contribution to journalArticle

Lim, Dae Sik ; Vogel, Hannes ; Willerford, Dennis M. ; Sands, Arthur T. ; Platt, Kenneth A. ; Hasty, Edward P. / Analysis of ku80-mutant mice and cells with deficient levels of p53. In: Molecular and Cellular Biology. 2000 ; Vol. 20, No. 11. pp. 3772-3780.
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