Reduced apoptosis and increased deletion mutations at Aprt locus in vivo in mice exposed to repeated ionizing radiation

Li Liang, Marc Mendonca, Li Deng, Son C. Nguyen, Changshun Shao, Jay A. Tischfield

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Exposure to ionizing radiation (IR) is a risk factor for carcinogenesis because it is a mutagen. However, a single 4-Gy whole body X-ray exposure only induced a modest increase of mutations at the Aprt reporter gene locus in mouse T cells. Intriguingly, when the same dose of IR was given in a fractionated protocol (1 Gy x 4 at weekly intervals), there was a strong induction of Aprt mutations in T cells. Many of these were mutations that arose via interstitial deletions inclusive of Aprt or by intragenic deletions. We hypothesized that the weekly fractionated X-ray exposures select for somatic cells with reduced p53 expression and/or reduced apoptosis, which, in turn, may have facilitated the accumulation of interstitial deletions, as in p53-deficient mice. We indeed found that splenocytes of mice with three previous exposures (1 Gy x 4 in total) were more resistant to X-ray-induced apoptosis than those of mice exposed to X-rays for the first time (1 Gy total). Thus, repeated X-ray radiation selects for reduced apoptosis in vivo. However, this reduced apoptosis is p53-independent, because p53 induction and the up-regulation of genes downstream of p53, such as Bax and p21, were similar between the 1-Gy and 1 Gy x 4 groups. Reduced apoptosis probably allows the generation of more mutations, particularly deletion mutations. Because both reduced apoptosis and increased somatic mutation are risk factors for carcinogenesis, they may contribute to the paradigm in which different radiation exposure schemes are varied in their efficiency in inducing lymphomagenesis.

Original languageEnglish
Pages (from-to)1910-1917
Number of pages8
JournalCancer Research
Volume67
Issue number5
DOIs
StatePublished - Mar 1 2007

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Sequence Deletion
Ionizing Radiation
X-Rays
Apoptosis
Mutation
Carcinogenesis
T-Lymphocytes
p53 Genes
Mutagens
Reporter Genes
Up-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Reduced apoptosis and increased deletion mutations at Aprt locus in vivo in mice exposed to repeated ionizing radiation. / Liang, Li; Mendonca, Marc; Deng, Li; Nguyen, Son C.; Shao, Changshun; Tischfield, Jay A.

In: Cancer Research, Vol. 67, No. 5, 01.03.2007, p. 1910-1917.

Research output: Contribution to journalArticle

Liang, Li ; Mendonca, Marc ; Deng, Li ; Nguyen, Son C. ; Shao, Changshun ; Tischfield, Jay A. / Reduced apoptosis and increased deletion mutations at Aprt locus in vivo in mice exposed to repeated ionizing radiation. In: Cancer Research. 2007 ; Vol. 67, No. 5. pp. 1910-1917.
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