The pathological response to DNA damage does not contribute to p53-mediated tumour suppression - PubMed (original) (raw)
. 2006 Sep 14;443(7108):214-7.
doi: 10.1038/nature05077. Epub 2006 Sep 6.
Affiliations
- PMID: 16957739
- DOI: 10.1038/nature05077
The pathological response to DNA damage does not contribute to p53-mediated tumour suppression
M A Christophorou et al. Nature. 2006.
Abstract
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.
Comment in
- Cancer biology: can less be more for p53?
Berns A. Berns A. Nature. 2006 Sep 14;443(7108):153-4. doi: 10.1038/443153a. Nature. 2006. PMID: 16971934 No abstract available.
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