The Toll-like receptor gene family is integrated into human DNA damage and p53 networks
Open accessAbstract
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.
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Rodents lack direct p53 responsiveness of the mouse TLR gene family, which precludes their use in developing human therapies based on p53 modulation of TLR responses.
“We note that while rodents have served as excellent models systems for addressing p53 functions the lack of direct p53 responsiveness of the mouse TLR gene family precludes their use in developing human therapies based on p53 modulation of TLR responses [24].”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [24]
In Results, ‘Evolution of TLR gene family responsiveness to p53’ (page not provided), the authors report small, apparently p53-independent TLR responses in the mouse cells tested and no predicted functional p53 targets among several mouse TLR sequences. This supports the distinction from human TLR responses, but the paper does not establish that rodents cannot be used to develop human therapies; ‘precludes their use’ is a stronger conclusion than these findings support. (LLM, conf=0.85)
Experimental — accuracy not yet measuredWild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses.
“We previously found that wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses.”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [24]
p53 can directly influence expression of the TLR gene family and downstream immune/inflammatory responses.
“Since p53 can directly influence expression of the TLR gene family and downstream immune/inflammatory responses [24–26]”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [24]
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- Authors
- Menendez, D., Shatz, M., Azzam, K., Garantziotis, S., Fessler, M. B., & Resnick, M. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Resnick, Michael A.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-03-31
- Volume
- 7
- Issue
- 3
- Pages
- e1001360
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3069118
- OpenAlex
- W2050089738
- Cited by
- 148
- References
- 45
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 15 · 2021: 8 · 2020: 5 · 2019: 10 · 2018: 11 · 2017: 9 · 2016: 13 · 2015: 17 · 2014: 11 · 2013: 11 · 2012: 13
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences (ES102005, Z01ES065079, Z01ES102005, ES065079)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- Toll-like receptors, p53, DNA damage response, innate immunity, transcriptional regulation, promoter response elements, alveolar macrophages, blood lymphocytes, anticancer agents, interindividual variability, primate evolution, cytokine induction
- MeSH terms
- Adolescent, Adult, Cells, Cultured, DNA Damage, Humans, Immunity, Innate, Lymphocytes, Macrophages, Male, Promoter Regions, Genetic, Stress, Physiological, Signal Transduction, Transcriptional Activation, Tumor Suppressor Protein p53, Evolution, Molecular, Polymorphism, Single Nucleotide, Cell Line, Tumor, Toll-Like Receptors, Gene Regulatory Networks, Young Adult
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