The pathological response to DNA damage does not contribute to p53-mediated tumour suppression.
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.
Christophorou
M A
MA
Cancer Research Institute and Department of Cellular & Molecular Pharmacology, Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA.
Ringshausen
I
I
Finch
A J
AJ
Swigart
L Brown
LB
Evan
G I
GI
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004249:DNA Damage / Q000528:radiation effects; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53