Christophorou MA, Ringshausen I, Finch AJ, Swigart LB, Evan GIThe pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443: 214-217

Cancer Research Institute and Department of Cellular & Molecular Pharmacology, Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA.
Nature (Impact Factor: 41.46). 10/2006; 443(7108):214-7. DOI: 10.1038/nature05077
Source: PubMed


The p53 protein has a highly evolutionarily conserved role in metazoans as 'guardian of the genome', mediating cell-cycle arrest and apoptosis in response to genotoxic injury. In large, long-lived animals with substantial somatic regenerative capacity, such as vertebrates, p53 is an important tumour suppressor--an attribute thought to stem directly from its induction of death or arrest in mutant cells with damaged or unstable genomes. Chemotherapy and radiation exposure both induce widespread p53-dependent DNA damage. This triggers potentially lethal pathologies that are generally deemed an unfortunate but unavoidable consequence of the role p53 has in tumour suppression. Here we show, using a mouse model in which p53 status can be reversibly switched in vivo between functional and inactive states, that the p53-mediated pathological response to whole-body irradiation, a prototypical genotoxic carcinogen, is irrelevant for suppression of radiation-induced lymphoma. In contrast, delaying the restoration of p53 function until the acute radiation response has subsided abrogates all of the radiation-induced pathology yet preserves much of the protection from lymphoma. Such protection is absolutely dependent on p19(ARF)--a tumour suppressor induced not by DNA damage, but by oncogenic disruption of the cell cycle.

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    • "This model was further used to show that the p53-mediated pathological response to whole-body irradiation, a prototypical genotoxic carcinogen, is irrelevant for suppression of radiation-induced lymphoma (Christophorou et al. 2006). In contrast, delaying the restoration of p53 function until the acute radiation response has subsided abrogates all of the radiation-induced pathology, yet preserves much of the protection from lymphoma (Christophorou et al. 2006). The p53ER TAM model was also used to explore the possibility of restoring p53 activity as a tumor therapy. "
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    • "p53, a multifunctional protein that has a role in DNA damage response associated with the cell's decision between apoptosis and other fates, has been extensively studied [1] [2]. However, the acute response by p53 clearly induces ''unnecessary apoptosis'' that does not contribute to tumor suppression [3]. Thus, p53 is considered to be a target for therapeutic and mitigative radioprotection for suppressing the excess apoptosis that is observed in highly radiosensitive organs, and chemical p53 inhibitors would be expected to selectively prevent the damage of normal tissues during radio (chemo) therapy for p53-deficient tumors [4]. "
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    • "We have now performed pathology on this cohort and found that 30% (3 out of 10) of the irradiated Mdm2P2/P2 and Mdm2+/+ mice also developed lymphomas. These data concur with a previous report that showed that pathological radiation response is irrelevant for suppression of lymphoma development later in life [29]. Together, these data indicate that enhanced acute p53 activity generated in the absence of the feedback loop does not protect against tumorigenesis. "
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