The Toll-Like Receptor Gene Family Is Integrated into Human DNA Damage and p53 Networks

Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
PLoS Genetics (Impact Factor: 7.53). 03/2011; 7(3):e1001360. DOI: 10.1371/journal.pgen.1001360
Source: PubMed


In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond "guardian of the genome." Our studies of promoter response element sequences targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive regulator in the control of human Toll-like receptor (TLR) gene expression. The TLR gene family mediates innate immunity to a wide variety of pathogenic threats through recognition of conserved pathogen-associated molecular motifs. Using primary human immune cells, we have examined expression of the entire TLR gene family following exposure to anti-cancer agents that induce the p53 network. Expression of all TLR genes, TLR1 to TLR10, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors. However, there is considerable inter-individual variability. Most of the TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites. Importantly, the integration of the TLR gene family into the p53 network is unique to primates, a recurrent theme raised for other gene families in our previous studies. Furthermore, a polymorphism in a TLR8 response element provides the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findings-demonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stress-have many implications for health and disease, as well as for understanding the evolution of damage and p53 responsive networks.

Download full-text


Available from: Stavros Garantziotis, Oct 03, 2015
17 Reads
  • Source
    • "DNA damage, such as strand breaks, could be induced by various agents among which H 2 O 2 produces a genotoxic effect. It is known that those damages can affect the immune response not only in inflammatory diseases but also in cancers [22] [23]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Trametes species have been used for thousands of years in traditional and conventional medicine for the treatment of various types of diseases. The goal was to evaluate possible antigenotoxic effects of mycelium and basidiocarp extracts of selected Trametes species and to assess dependence on their antioxidant potential. Trametes versicolor, T. hirsuta, and T. gibbosa were the species studied. Antigenotoxic potentials of extracts were assessed on human peripheral white blood cells with basidiocarp and mycelium extracts of the species. The alkaline comet test was used for detection of DNA strand breaks and alkali-labile sites, as well as the extent of DNA migration. DPPH assay was used to estimate antioxidative properties of extracts. Fruiting body extracts of T. versicolor and T. gibbosa as well as T. hirsuta extracts, except that at 20.0 mg/mL, were not genotoxic agents. T. versicolor extract had at 5.0 mg/mL the greatest antigenotoxic effect in both pre- and posttreatment of leukocytes. The mycelium extracts of the three species had no genotoxic activity and significant antigenotoxic effect against H2O2-induced DNA damage, both in pre- and posttreatment. The results suggest that extracts of these three species could be considered as strong antigenotoxic agents able to stimulate genoprotective response of cells.
    The Scientific World Journal 08/2015; 2015(2):146378. DOI:10.1155/2015/146378 · 1.73 Impact Factor
  • Source
    • "ATF3 modulated the transcription of IL-6, IL-12b, and IL-12p40, which highlights its key regulatory roles in TLR signaling. Recent studies have further reported that TLR gene expression closely interacts with that of p53 (10,11). The hypothesis that ATF3 can modulate the activity of p53 was based on evidence supporting the interaction between these two proteins (12). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epilepsy is a common and often deleterious neurological condition. Emerging evidence has demonstrated the roles of innate immunity and the associated inflammatory processes in epilepsy. In a previous study, we found that Toll‑like receptors (TLRs) are upregulated and promote mossy fiber sprouting (MFS) in an epileptic model. As downstream effectors of TLRs, the activating transcription factor 3 (ATF3) and p53 proteins were shown to be involved in neurite outgrowth. In the present study, we hypothesized that ATF3 and p53 participate in the process of epilepsy and can affect MFS. To investigate this hypothesis, we examined the expression of ATF3 and p53 in hippocampal tissues of rats kindled by pentylenetetrazole (PTZ) using immunofluorescence, immunohistochemistry and western blotting. MFS was evaluated by Timm staining in the hippocampus. Results from these experiments revealed that expression of ATF3 and p53 is significantly higher (p<0.05) in the CA3 area of the hippocampus in the PTZ-treated group compared to the control group. ATF3 expression gradually increased from 3 days to 4 weeks, peaked at 4 weeks and decreased slightly at 6 weeks in the PTZ group, while the expression of p53 was maintained at similar levels at different time‑points following PTZ treatment. No obvious difference in the expression of these proteins was observed between the PTZ and the control group in the dentate gyrus (DG) area (p>0.05). The degree of MFS in the PTZ group peaked at 4 weeks and was maintained at a high level until 6 weeks post‑PTZ treatment. In conclusion, ATF3 and p53 may be involved in the occurrence of seizure and play critical roles in MFS in the PTZ kindling model.
    Molecular Medicine Reports 05/2014; 10(2). DOI:10.3892/mmr.2014.2256 · 1.55 Impact Factor
  • Source
    • "Complementary DNAs were generated from 1 µg of purified RNA using TaqMan reverse transcription reagents from Applied Biosystems (Foster City, CA). qPCR was performed on an HT7900 system (Applied Biosystems) using pre-validated primers for the indicated genes, as previously described (8). Relative quantification values were calculated based on the 2-ΔΔCt method and using expression from β-2-microglobulin or GAPDH for normalization. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The effects of diverse stresses on promoter selectivity and transcription regulation by the tumor suppressor p53 are poorly understood. We have taken a comprehensive approach to characterizing the human p53 network that includes p53 levels, binding, expression and chromatin changes under diverse stresses. Human osteosarcoma U2OS cells treated with anti-cancer drugs Doxorubicin (DXR) or Nutlin-3 (Nutlin) led to strikingly different p53 gene binding patterns based on chromatin immunoprecipitation with high-throughput sequencing experiments. Although two contiguous RRRCWWGYYY decamers is the consensus binding motif, p53 can bind a single decamer and function in vivo. Although the number of sites bound by p53 was six times greater for Nutlin than DXR, expression changes induced by Nutlin were much less dramatic compared with DXR. Unexpectedly, the solvent dimethylsulphoxide (DMSO) alone induced p53 binding to many sites common to DXR; however, this binding had no effect on target gene expression. Together, these data imply a two-stage mechanism for p53 transactivation where p53 binding only constitutes the first stage. Furthermore, both p53 binding and transactivation were associated with increased active histone modification histone H3 lysine 4 trimethylation. We discovered 149 putative new p53 target genes including several that are relevant to tumor suppression, revealing potential new targets for cancer therapy and expanding our understanding of the p53 regulatory network.
    Nucleic Acids Research 06/2013; 41(15). DOI:10.1093/nar/gkt504 · 9.11 Impact Factor
Show more