p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis

Abstract

Mice constitutively lacking alleles of the p53 tumour suppressor gene spontaneously develop lymphomas and sarcomas. We report here that a single dose of 4 Gy radiation dramatically decreases the latency for tumour development in p53 heterozygous mice. The pattern of genetic alterations at the remaining wild type allele in these tumours differs substantially from spontaneous tumours from similar mice indicating that p53 itself may have been a target for radiation-induced alterations. Lower dose irradiation (1 Gy) of preweanling p53 null mice also significantly decreases tumour latency, suggesting that there are additional genetic targets involved in radiation-induced malignancy. Thus p53-deficient mice provide a sensitive model system for studies of the consequences of radiation exposure.

Li-Fraumeni syndrome – a molecular and clinical review

“…TP53-deficient mice are extremely sensitive to gamma irradiation with a reduced tumour latency following low-level irradiation (Kemp et al, 1994). This sensitivity is associated with an increase in radiation-induced double-strand chromosomal breaks .…”

Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53±murine model

“…18 In p53 ±/- heterozygous mice, which shows only moderate tumor susceptibility, gamma radiation dramatically reduces the latency of tumor development. 19-21 Due to irradiation induced mutations, the intact wild type p53 allele is mutated in p53 +/- tumors, resulting in loss of heterozygosity (LOH), no functional p53 expression, and tumor growth. 19 Importantly, synergy between p53 inactivation and other mutations lead to the emergence of specific tumor types such as p53 loss in Kras G12D knock-in leads to AML 22 or Eμ-myc transgene to B cell lymphomas.…”

An Eμ-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation

“…We reasoned that with apoptosis inhibited in B lineage cells by constitutive over-expression of a BCL-2 transgene, genotoxic damage might lead to an alternative pathway of DNA repair, mis-repair or mutation. This possibility was endorsed by the precedent that abrogation of the irradiation-induced apoptotic pathway in lymphoid cells via loss of p53 results in survival of Xirradiation-induced clonogenic mutants (Gri ths et al, 1997), a high level of spontaneous leukaemia (Donehower et al, 1992;Jacks et al, 1994;Purdie et al, 1994) and an accelerated X-irradiation-induced leukaemia in young homozygous (7/7) or heterozygous (+/7) p53 knockout mice (Kemp et al, 1994).…”