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Cited by 167Genomics, phytochemicals, and oxidative stressNF-κB Signaling PathwaysSignaling Pathways in Disease

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Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis

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Nair, S, Doh, S T, Chan, J Y, Kong, A-N, Cai, L·2008·British Journal of Cancer
DOI 10.1038/sj.bjc.6604703PMC PMC2607222
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Abstract

Many studies have implicated nuclear factor E2-related factor 2 (Nrf2) and nuclear factor-kappaB1 (Nfkb1) in inflammation and cancer. However, the regulatory potential for crosstalk between these two important transcription factors in inflammation and carcinogenesis has not been explored. To delineate conserved transcription factor-binding site signatures, we performed bioinformatic analyses on the promoter regions of human and murine Nrf2 and Nfkb1. We performed multiple sequence alignment of Nrf2 and Nfkb1 genes in five mammalian species - human, chimpanzee, dog, mouse and rat - to explore conserved biological features. We constructed a canonical regulatory network for concerted modulation of Nrf2 and Nfkb1 involving several members of the mitogen-activated protein kinase (MAPK) family and present a putative model for concerted modulation of Nrf2 and Nfkb1 in inflammation/carcinogenesis. Our results reflect potential for putative crosstalk between Nrf2 and Nfkb1 modulated through the MAPK cascade that may influence inflammation-associated etiopathogenesis of cancer. Taken together, the elucidation of potential relationships between Nrf2 and Nfkb1 may help to better understand transcriptional regulation, as well as transcription factor networks, associated with the etiopathogenesis of inflammation and cancer.

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Figures

Figure 1 (A) A conserved TFBS between mouse Nfe2l2 and Nfkb1. Vertebrate (V$) matrix families conserved between murine Nfe2l2 and Nfkb1 promoter regions were identified using Genomatix MatInspector. (B) A conserved TFBS between human NFE2L2 and NFKB1. Vertebrate (V$) matrix families conserved between human NFE2L2 and NFKB1 promoter regions were identified using Genomatix MatInspector.
Figure 1 (A) A conserved TFBS between mouse Nfe2l2 and Nfkb1. Vertebrate (V$) matrix families conserved between murine Nfe2l2 and Nfkb1 promoter regions were identified using Genomatix MatInspector. (B) A conserved TFBS between human NFE2L2 and NFKB1. Vertebrate (V$) matrix families conserved between human NFE2L2 and NFKB1 promoter regions were identified using Genomatix MatInspector.CC BY · PubMed Central
Figure 2 Multiple species alignment. Non-coding sequences of Nfe2l2 and Nfkb1 genes in five mammalian species – human, chimpanzee, dog, mouse and rat – were retrieved using the Non-Coding Sequence Retrieval System (NCSRS) for comparative genomic analysis of gene regulatory elements. Multiple sequence alignment was performed by submitting the non-coding sequences to MLAGAN and visualised by projecting them to pairwise alignments with respect to one reference sequence (human) as baseline. Pink regions, conserved non-coding sequences (CNS); dark blue regions, exons. The numbers indicate CNS that were identified across species. (A) Multiple species alignment for Nfe2l2; (B) multiple species alignment for Nfkb1; (C) phylogenetic tree for Nfe2l2 and Nfkb1; (D) a conserved TFBS between NFE2L2 and NFKB1 among top matching human sequences.
Figure 2 Multiple species alignment. Non-coding sequences of Nfe2l2 and Nfkb1 genes in five mammalian species – human, chimpanzee, dog, mouse and rat – were retrieved using the Non-Coding Sequence Retrieval System (NCSRS) for comparative genomic analysis of gene regulatory elements. Multiple sequence alignment was performed by submitting the non-coding sequences to MLAGAN and visualised by projecting them to pairwise alignments with respect to one reference sequence (human) as baseline. Pink regions, conserved non-coding sequences (CNS); dark blue regions, exons. The numbers indicate CNS that were identified across species. (A) Multiple species alignment for Nfe2l2; (B) multiple species alignment for Nfkb1; (C) phylogenetic tree for Nfe2l2 and Nfkb1; (D) a conserved TFBS between NFE2L2 and NFKB1 among top matching human sequences.CC BY · PubMed Central
Figure 3 A canonical regulatory network for Nrf2–Nfkb1 interactions in inflammation-associated carcinogenesis. (A) A putative regulatory network for Nrf2 (Nfe2l2) and Nfkb1 representing 59 nodes and 253 potential interactions implicating several members of the MAPK family; (B) literature network in humans; (C) literature network in mice; (D) functional crosstalk in biological network of Nfe2l2, Nfkb1 and various members of the MAPK cascade; (E) differential expression of MAPKs in cancer vs developmental or non-cancerous tissue/cell lines (GSM116104–116106: bronchial smooth muscle cells; GSM133871–133873: retinal pigment epithelial cell line; GSM156176–156178: skeletal muscle; GSM187371–187373: untreated LNCaP cells; GSM211446–211448: normal adrenal gland; GSM286756–286758: untreated MCF7 cells; GSM74875–74880: benign prostate tissue; GSM74881–74887: clinically localised primary prostate cancer; GSM74888–74893: metastatic prostate cancer).
Figure 3 A canonical regulatory network for Nrf2–Nfkb1 interactions in inflammation-associated carcinogenesis. (A) A putative regulatory network for Nrf2 (Nfe2l2) and Nfkb1 representing 59 nodes and 253 potential interactions implicating several members of the MAPK family; (B) literature network in humans; (C) literature network in mice; (D) functional crosstalk in biological network of Nfe2l2, Nfkb1 and various members of the MAPK cascade; (E) differential expression of MAPKs in cancer vs developmental or non-cancerous tissue/cell lines (GSM116104–116106: bronchial smooth muscle cells; GSM133871–133873: retinal pigment epithelial cell line; GSM156176–156178: skeletal muscle; GSM187371–187373: untreated LNCaP cells; GSM211446–211448: normal adrenal gland; GSM286756–286758: untreated MCF7 cells; GSM74875–74880: benign prostate tissue; GSM74881–74887: clinically localised primary prostate cancer; GSM74888–74893: metastatic prostate cancer).CC BY · PubMed Central
Figure 4 A putative model for Nrf2-–Nfkb1 interactions in inflammation and carcinogenesis. Chemical signals generated by dietary chemopreventive agents or toxicants, or inflammatory signals, may cause Nrf2 nuclear translocation that sets in motion a dynamic machinery of coactivators and corepressors that may form a multimolecular complex with Nrf2 for modulating transcriptional response through the antioxidant response element, ARE. Inflammation may also cause release of NF-κB from IκB and stimulate NF-κB nuclear translocation to modulate transcriptional response through the NF-κB response element, NF-κB-RE, along with the cofactors of NF-κB. Several members of the MAPK family may act in concert with Nrf2 and Nfkb1 with multiple interactions between the members of the putative complex to elicit the chemopreventive and pharmacotoxicological events in inflammation and carcinogenesis.
Figure 4 A putative model for Nrf2-–Nfkb1 interactions in inflammation and carcinogenesis. Chemical signals generated by dietary chemopreventive agents or toxicants, or inflammatory signals, may cause Nrf2 nuclear translocation that sets in motion a dynamic machinery of coactivators and corepressors that may form a multimolecular complex with Nrf2 for modulating transcriptional response through the antioxidant response element, ARE. Inflammation may also cause release of NF-κB from IκB and stimulate NF-κB nuclear translocation to modulate transcriptional response through the NF-κB response element, NF-κB-RE, along with the cofactors of NF-κB. Several members of the MAPK family may act in concert with Nrf2 and Nfkb1 with multiple interactions between the members of the putative complex to elicit the chemopreventive and pharmacotoxicological events in inflammation and carcinogenesis.CC BY · PubMed Central

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Metadata

Authors
Nair, S., Doh, S. T., Chan, J. Y., Kong, A.-N., & Cai, L.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • University of California, Irvine (US)
Corresponding author
Cai, L
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2008-12
Volume
99
Issue
12
Pages
2070-2082
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/sj.bjc.6604703
PMC
PMC2607222
OpenAlex
W2059649811
Cited by
167
References
58
Citations by year
2026: 8 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 11 · 2021: 8 · 2020: 13 · 2019: 13 · 2018: 10 · 2017: 16 · 2016: 13 · 2015: 11 · 2014: 7 · 2013: 8 · 2012: 10
FWCI
2.20
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Cancer Institute (CA133675, R01CA094828, R21CA133675)
  • National Institute of Environmental Health Sciences (P30ES005022)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
Nrf2, NFKB1, transcription factor crosstalk, inflammation, carcinogenesis, MAPK signaling, transcription factor binding sites, promoter analysis, transcriptional regulation, inflammation-associated cancer
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Cell Transformation, Neoplastic, Humans, Inflammation, Molecular Sequence Data, Gene Expression Regulation, Neoplastic, Sequence Alignment, Conserved Sequence, Computational Biology, Microarray Analysis, NF-E2-Related Factor 2, Mice, Rats, NF-kappa B p50 Subunit

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