Cited by 37Pharmacogenetics and Drug MetabolismNuclear Receptors and SignalingEstrogen and related hormone effects

In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets

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Niu, Ben, Coslo, Denise M, Bataille, Alain R, Albert, Istvan, Pugh, B Franklin, Omiecinski, Curtis J·2018·Nucleic Acids Research

Abstract

The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.

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Crossref · 10.1093/nar/gky692

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  • The effects of the CAR-driven c-Myc-Foxm1 axis are not recapitulated in humanized CAR transgenic mice or human hepatocytes.

    “these effects are not recapitulated in humanized CAR transgenic mice or human hepatocytes,45, 46, 47”

    From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [45]

    The Discussion (page unavailable) reports much weaker Myc induction in humanized CAR mice than in wild-type mice, supporting a species difference, but not a complete absence of the effect. The Results (page unavailable) do not establish that a c-Myc–Foxm1 axis fails to occur in human hepatocytes; the paper discusses FOXO3, not Foxm1, in relation to Myc. (LLM, conf=0.86)

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  1. [63]Dussault I., Lin M., Hollister K., Fan M., Termini J., Sherman M.A., Forman B.M. A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity. Mol. Cell. Biol. 2002; 22: 5270– 5280. 12101224 PMC133936
  2. [69]Wong C.M., Fan S.T., Ng I.O. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer. 2001; 92: 136– 145. 11443619

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Authors
Niu, B., Coslo, D. M., Bataille, A. R., Albert, I., Pugh, B. F., & Omiecinski, C. J.
Affiliations
Pennsylvania State University (US)
Corresponding author
Omiecinski, Curtis J
Venue
Nucleic Acids Research
Published
2018-08-08
Volume
46
Issue
16
Pages
8385-8403
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
OpenAlex
W2890819992
Cited by
37
References
74
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 2 · 2018: 3
FWCI
5.23
Type
journal article
Language
en
Open access
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (GM066411)
  • National Environmental Health Sciences Institute (ES013768)
  • U.S. Department of Agriculture (2014-06624)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
constitutive androstane receptor, nuclear receptor binding sites, species differences, human-mouse comparison, liver tumor promotion, GDF15, FOXO3, c-Myc, IKBKE, transcriptional regulation, binding motifs, liver cell proliferation, ChIP-exo
MeSH terms
Forkhead Box Protein O3, Constitutive Androstane Receptor, Androstanes, Animals, DNA-Binding Proteins, Humans, Ligands, Liver, Liver Neoplasms, Mice, Transgenic, Protein Binding, Genes, myc, Genome, Receptors, Cytoplasmic and Nuclear, Hepatocytes, Cell Proliferation, Mice, I-kappa B Kinase, Growth Differentiation Factor 15

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