Meek DW.. Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer 9: 714-723

Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
Nature Reviews Cancer (Impact Factor: 29.54). 10/2009; 9(10):714-23. DOI: 10.1038/nrc2716
Source: PubMed

ABSTRACT Loss of p53 function occurs during the development of most, if not all, tumour types. This paves the way for genomic instability, tumour-associated changes in metabolism, insensitivity to apoptotic signals, invasiveness and motility. However, the nature of the causal link between early tumorigenic events and the induction of the p53-mediated checkpoints that constitute a barrier to tumour progression remains uncertain. This Review considers the role of the DNA damage response, which is activated during the early stages of tumour development, in mobilizing the tumour suppression function of p53. The relationship between these events and oncogene-induced p53 activation through the ARF pathway is also discussed.

    • "Our findings and results of other studies of the role of CTAs in the regulation of proliferation and apoptoo sis in tumor cells provide the grounds for suggesting that the CTA expression in MEFs may be associated with cell response to various stress factors, as in celluu lar aging and exposure to cytostatic mitomycin C. It is known that various damaging factors (heat shock, radiation, hypoxia, and DNAAdamaging factors) actii vate p533dependent pathways that promote cell cycle arrest to start the repair or apoptosis of injured cells (Riley et al., 2008; Meek, 2009; Suvorova et al., 2012; Eichhorn et al., 2013). Cytostatic effect of protein p53 is mediated by uppregulation of expression of the proo tein regulator of the cell cycle, p21 Cip1 . "
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    ABSTRACT: Cancer-testis antigens are expressed in the spermatogenic and cancer cells, as well as in human and mouse pluripotent stem cells. However, the role of cancer-testis antigens of Mage families in the regulation of cellular processes in embryonic cells is largely unknown. In the present study, a comparative quantitative analysis of the Mage-a and Mage-b gene expression was performed in mouse embryonic somatic cells (mouse embryonic fibroblasts, MEFs) long-term cultured in vitro or exposed to factors that inhibit and stimulate proliferation. The analysis revealed a low expression of cancer-testis antigens of Mage families and showed that the decrease in proliferative activity of MEFs at late passages was accompanied by slight up-regulation of the Mage-a gene expression and down-regulation of Mage-b gene expression. However, modulation of the MEK/ERK-signaling pathway activity and DNA demethylation with 5-azacytidine had no significant effects on the Mage-a and Mage-b gene expression in MEFs. The most essential changes in the expression levels of Mage-a and Mage-b genes were found only when MEFs were exposed to mitomycin C. In all experimental variants, the predominant cytoplasmic localization of Mage antigens was found in MEFs at the DNA synthesis stage, as well as at other stages of the cell cycle. Presumably, in actively proliferating mouse embryonic somatic cells, the antigens of Mage-a and Mage-b families can act as coactivators in the regulation of cell proliferation and other cellular processes.
    Russian Journal of Developmental Biology 05/2015; 46(3):148-158. DOI:10.1134/S1062360415030030 · 0.22 Impact Factor
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    • "We also further analyzed the known p53 target Eda2r, because it was the most significantly regulated gene in each of the four separate experiments, indicating the importance of this gene in the p53-mediated response in the brain. The early activation of p53 at 2 h postirradiation was first demonstrated by western blotting using an antibody against the phosphorylated form of p53 at the serine 15 residue (Fig. 4A), which is the main target of the DNA damage response to radiation (Meek, 2009). Next, we performed qRT- PCR on brains from control and 1 Gy X-irradiated p53 +/+ , p53 "
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    ABSTRACT: Ionizing radiation is a potent activator of the tumor suppressor gene p53, which itself regulates the transcription of genes involved in canonical pathways such as the cell cycle, DNA repair and apoptosis as well as other biological processes like metabolism, autophagy, differentiation and development. In this study, we performed a meta-analysis on gene expression data from different in vivo and in vitro experiments to identify a signature of early radiation-responsive genes which were predicted to be predominantly regulated by p53. Moreover, we found that several genes expressed different transcript isoforms after irradiation in a p53-dependent manner. Among this gene signature, we identified novel p53 targets, some of which have not yet been functionally characterized. Surprisingly, in contrast to genes from the canonical p53-regulated pathways, our gene signature was found to be highly enriched during embryonic and post-natal brain development and during in vitro neuronal differentiation. Furthermore, we could show that for a number of genes, radiation-responsive transcript variants were upregulated during development and differentiation, while radiation non-responsive variants were not. This suggests that radiation exposure of the developing brain and immature cortical neurons results in the p53-mediated activation of a neuronal differentiation program. Overall, our results further increase the knowledge of the radiation-induced p53 network of the embryonic brain and provide more evidence concerning the importance of p53 and its transcriptional targets during mouse brain development.
    Biology Open 02/2015; DOI:10.1242/bio.20149969 · 2.42 Impact Factor
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    • "Therefore, exploring the complex formations of DNA with OPFRs is considered as an important step to provide valuable information about the genotoxicity and carcinogenicity of OPFRs. p53 is a short-lived transcription factor that has been most extensively studied in its capacity to mediate innate tumor suppression (Vousden and Lane, 2007; Meek, 2009). In animal models, loss or mutation of p53 predisposes to a range of spontaneous and induced tumors (Iwakuma and Lozano, 2007), highlighting its protective role as a barrier to tumor development. "
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    ABSTRACT: Health concerns have been raised in regards to the environmental impact of the more frequently used organophosphate flame retardants (OPFRs). In this study, the effects of two typical OPFRs (TCPP and TPhP) on p53 gene expression in human embryo liver L02 cells were determined by quantitative Real-time PCR. To better understand the relationship between molecular structural features of OPFRs and binding affinities for the tumor suppressor genes p53, an integrated experimental and in silico approach was used. The interaction of 9 OPFRs with p53 DNA fragment under simulated physiological conditions (phosphate buffer solution of pH 7.40), was explored by UV absorption spectroscopy, fluorescence spectroscopy and molecular modeling method. The binding constants of 9 OPFRs with p53 DNA fragment were determined respectively, using ethidium bromide (EB) as fluorescence probe of DNA. From docking analysis, hydrogen bonding and hydrophobic interactions were found to be the dominant interactions. Based on the observed interactions, appropriate molecular structural parameters were adopted to develop a quantitative structure-activity relationship (QSAR) model. The binding affinities of OPFRs to p53 DNA fragment were related with molecular electrostatic potential. The developed QSAR model had good robustness, predictive ability and mechanism interpretability. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Toxicology Letters 12/2014; 232(2). DOI:10.1016/j.toxlet.2014.12.006 · 3.36 Impact Factor
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