Article

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: 37.4). 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.

1 Follower
 · 
32 Reads
  • Source
    • "Hence, it is important to understand how MaSCs maintain their genome integrity and how they react to DNA damage. In addition, mutation or loss of function of p53, a tumor suppressor gene that plays a major role in DDR (Meek, 2009), is correlated not only with mammary tumorigenesis but also with poor prognosis and treatment response in breast cancer (Bergh et al., 1995; Berns et al., 2000; Gasco et al., 2002; Sørlie et al., 2001). Therefore, dissecting the effects of p53 loss on DDR in mammary epithelium , especially in MaSCs, is particularly important for understanding breast cancer tumorigenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult stem cells and tumor-initiating cells (TICs) often employ different mechanisms of DNA damage response (DDR) as compared to other tissue cell types. However, little is known about how mammary stem cells (MaSCs) and mammary TICs respond to DNA damage. Using the mouse mammary gland and syngeneic p53-null tumors as models, we investigated the molecular and physiological consequences of DNA damage in wild-type MaSCs, p53-null MaSCs, and p53-null TICs. We showed that wild-type MaSCs and basal cells are more resistant to apoptosis and exhibit increased non-homologous end joining (NHEJ) activity. Loss of p53 in mammary epithelium affected both cell-cycle regulation and DNA repair efficiency. In p53-null tumors, we showed that TICs are more resistant to ionizing radiation (IR) due to decreased apoptosis, elevated NHEJ activity, and more-rapid DNA repair. These results have important implications for understanding DDR mechanisms involved in both tumorigenesis and therapy resistance. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Stem Cell Reports
    • "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 . "
    [Show abstract] [Hide abstract]
    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 comparative quantitative analysis of the gene expression of Magea and Mageb families was performed in mouse embryonic somatic cells (mouse embryonic fibroblasts, MEFs), long-term cultured in vitro and exposed to factors that inhibit and stimulate proliferation. The analysis revealed low expression of cancer-testis antigens of Mage families and showed that a lower proliferative activity of MEF at late passages was accompanied by slight up-regulation of the Magea gene expression and down-regutation of Mageb gene expression. However, modulation of the activity of MEK/ERK-signaling pathway and DNA demethylation by 5-azacytidine had no significant effects on the expression of Magea and Mageb genes in M EFs. The most essential changes in the expression levels of Mageb and Magea genes were found only when MEFs were exposed to mitomycin C. In all experimental variants, predominantly cytoplasmic localization of Mage antigens was found in MEFs at the phase of DNA synthesis, as well as at other cell cycle phases. Presumably, in actively proliferating mouse embryonic somatic cells the antigens of Magea and Mageb families can act as co-activators in the regulation of cell proliferation and other cellular functions.
    No preview · Article · May 2015 · Ontogenez
    • "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 . "
    [Show abstract] [Hide abstract]
    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.
    No preview · Article · May 2015 · Russian Journal of Developmental Biology
Show more