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Cited by 29Immune Response and InflammationCancer-related Molecular PathwaysNF-κB Signaling Pathways

p53 amplifies Toll-like receptor 5 response in human primary and cancer cells through interaction with multiple signal transduction pathways

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Shatz, Maria, Shats, Igor, Menendez, Daniel, Resnick, Michael A.·2015·Oncotarget
DOI 10.18632/oncotarget.4435PMC PMC4627285
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Abstract

// Maria Shatz 1 , Igor Shats 2 , Daniel Menendez 1 and Michael A. Resnick 1 1 Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA 2 Department of Biomedical Engineering, Duke University, Durham, NC, USA Correspondence to: Maria Shatz, email: // Michael A. Resnick, email: // Keywords : p53, Toll-like receptor 5, cancer, signal transduction, inflammation Received : February 06, 2015 Accepted : June 02, 2015 Published : June 10, 2015 Abstract The p53 tumor suppressor regulates transcription of genes associated with diverse cellular functions including apoptosis, growth arrest, DNA repair and differentiation. Recently, we established that p53 can modulate expression of Toll-like receptor (TLR) innate immunity genes but the degree of cross-talk between p53 and TLR pathways remained unclear. Here, using gene expression profiling we characterize the global effect of p53 on the TLR5-mediated transcription in MCF7 cells. We found that combined activation of p53 and TLR5 pathways synergistically increases expression of over 200 genes, mostly associated with immunity and inflammation. The synergy was observed in several human cancer cells and primary lymphocytes. The p53-dependent amplification of transcriptional response to TLR5 activation required expression of NFκB subunit p65 and was mediated by several molecular mechanisms including increased phosphorylation of p38 MAP kinase, PI3K and STAT3 signaling. Additionally, p53 induction increased cytokine expression in response to TNFα, another activator of NFκB and MAP kinase pathways, suggesting a broad interaction between p53 and these signaling pathways. The expression of many synergistically induced genes is elevated in breast cancer patients responsive to chemotherapy. We suggest that p53’s capacity to enhance immune response could be exploited to increase antitumor immunity and to improve cancer treatment.

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  • 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.

    “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 [26]

    The Introduction says p53 induction alters expression of TLR family genes in human primary leukocytes and cancer cell lines, and the Results describe enhanced cytokine responses to TLR ligands. The copy does not establish the claim’s more specific assertion that p53 regulates *most* TLR genes. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Nutlin, an activator of WT p53 functions, can greatly enhance the TLR5 downstream mediated responses to its natural ligand flagellin.

    “We recently demonstrated that Nutlin, an activator of WT p53 functions, can greatly enhance the TLR5 downstream mediated responses to its natural ligand flagellin [26].”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [26]

  • 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 [26]

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Authors
Shatz, M., Shats, I., Menendez, D., & Resnick, M. A.
Affiliations
  • National Institutes of Health (US)
  • Duke University (US)
  • Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2015-06-10
Volume
6
Issue
19
Pages
16963-16980
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.4435
PMC
PMC4627285
OpenAlex
W2103427285
Cited by
29
References
3
Citations by year
2026: 1 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 2
FWCI
1.48
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (ES065079)
  • National Institute of Environmental Health Sciences (Z01ES065079)
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 › Cancer Research › NF-κB Signaling Pathways
Keywords
p53, TLR5, NF-κB p65, p38 MAPK, PI3K signaling, STAT3 signaling, TNF-α, cytokine expression, inflammation, innate immunity, breast cancer, MCF-7 cells, gene expression profiling, antitumor immunity, chemotherapy response
MeSH terms
Humans, Immunity, Innate, Neoplasms, Transfection, Blotting, Western, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, RNA, Small Interfering, Cell Line, Tumor, Chromatin Immunoprecipitation, Toll-Like Receptor 5, Transcriptome

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