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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Available from: Lamorna Brown Swigart
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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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    ABSTRACT: In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated mice because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53-inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53-dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription-dependent events than pifithrin-μ (PFTμ), an inhibitor of transcription-independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription-dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2. AS-2 also protected mice that had been exposed to a lethal dose of ionizing radiation. Our findings indicate that some types of bidentate 8HQ chelators could serve as radioprotectors with no substantial toxicity in vivo.
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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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    ABSTRACT: The p53-Mdm2 feedback loop is thought to be the main mechanism by which p53 autoregulates its levels and activity after DNA damage. We tested this paradigm in a genetically engineered mouse model in which the feedback loop was disrupted by point mutations in the p53 binding site of the Mdm2 promoter. We noted that while the p53-Mdm2 feedback loop is required to regulate p53 activity especially in the hematopoietic system in response to DNA damage, its role in development and in regulating the stability of p53 is dispensable. In the present study we have extended our characterization of this mouse model and show that the kinetics of p53 degradation is also unchanged in mouse embryonic fibroblasts (MEFs). Additionally, MG132 experiments indicate that other E3-ligases regulate p53 stability. Also, Mdm4 cooperates in inhibition of p53 activity and levels in these mice. Finally, we show in this system that enhanced acute p53 response does not promote aging or protect against late term tumorigenesis. We also discuss future perspectives for this study.
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