Cited by 136Genomics, phytochemicals, and oxidative stressGlutathione Transferases and PolymorphismsPharmacogenetics and Drug Metabolism

Transcription factor Nrf2/MafK regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis

Open access
IKEDA, Hiromi, NISHI, Shinzo, SAKAI, Masaharu·2004·Biochemical Journal

Abstract

The rat GST-P (placental glutathione S-transferase), a phase II detoxifying enzyme, is not expressed in normal liver cells, but is highly and specifically induced during early hepatocarcinogenesis as well as in hepatocellular carcinoma cells. Results of previous studies indicated that GST-P gene activation was mainly controlled by an enhancer element, GPE1 (GST-P enhancer 1), but the specific activation mechanism of the GST-P gene was not fully understood [Morimura, Suzuki, Hochi, Yuki, Nomura, Kitagawa, Nagatsu, Imagawa and Muramatsu (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2065-2068; Suzuki, Imagawa, Hirabayashi, Yuki, Hisatake, Nomura, Kitagawa and Muramatsu (1995) Cancer Res. 55, 2651-2655]. In the present study, we investigate the transcription factor Nrf2/MafK heterodimer (where Nrf2 stands for NF-E2 p45-related factor 2) as an activator of the GST-P gene through the action of GPE1 during hepatocarcinogenesis. Electrophoretic mobility-shift assay and footprinting analysis with wild-type GPE1 and GPE1 point mutants showed that the Nrf2/MafK heterodimer specifically bound GPE1. Reporter transfection assays indicated that Nrf2 strongly stimulated GST-P gene expression in mouse F9 embryonal carcinoma cells and H4IIE rat hepatoma cells. Northern-blot analysis indicated that GST-P and Nrf2 mRNA increased in parallel with development of precancerous lesions and hepatocellular carcinoma. Keap1 (Kelch-like ECH-associated protein 1), an inhibitory factor of Nrf2, decreased the activation of GPE1 by Nrf2 and this suppression was restored after treatment with electrophilic compounds. GST-P mRNA expression in H4IIE cells was induced by electrophilic compounds, as was the expression of mRNAs of other phase II detoxifying enzymes. Chromatin immunoprecipitation analyses showed that antibodies both against Nrf2 and against MafK precipitated GPE1 from the chromatin of the pre-neoplastic hepatocytes and rat hepatoma cells (H4IIE and dRLh84), but not from normal hepatocytes. These results indicate that the Nrf2/MafK heterodimer regulates GST-P gene expression during early hepatocarcinogenesis and in hepatoma cells.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1042/bj20031948

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Aberrant Nrf2 expression and poor prognosis have been revealed in a wide range of cancers, including lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas.

    “numerous studies have revealed aberrant Nrf2 expression and poor prognosis in a wide range of cancers, including, among others, lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas [161,162,169,170,171,173,174]”

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Sambrook, J., Fritsch, E. F. and Maniatis, Y. (1989) Assay for β-galactosidase in extracts of mammalian cells. In Molecular Cloning: A Laboratory Manual, 2nd edn, pp. 16.66-16. 67, Cold Spring Harbor Laboratory Press, Plainview, NY 34
  2. Sambrook, J., Fritsch, E. F. and Maniatis, Y. (1989) Sequencing by the Maxam-Gilbert Method: A Laboratory Manual, 2nd edn, pp. 13.78-13.104, Cold Spring Harbor Laboratory Press, Plainview, NY

Cited by

Sorted by citations

Authors
IKEDA, H., NISHI, S., & SAKAI, M.
Affiliations
Hokkaido University (JP)
Venue
Biochemical Journal
Published
2004-06-01
Volume
380
Issue
2
Pages
515-521
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
OpenAlex
W2127462380
Cited by
136
References
39
Citations by year
2025: 2 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 2 · 2015: 6 · 2014: 9 · 2013: 11 · 2012: 9
FWCI
3.44
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Hokkaido University
  • Saitama Medical University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
glutathione S-transferase placental, glutathione S-transferase pi, hepatocarcinogenesis, hepatocellular carcinoma, Keap1, electrophilic compounds, phase II enzymes, transcriptional regulation, Nrf2, MafK, rat liver, H4IIE cells
MeSH terms
Kelch-Like ECH-Associated Protein 1, Acetylation, Animals, Chromatin, DNA-Binding Proteins, Enhancer Elements, Genetic, Glutathione Transferase, Carcinoma, Hepatocellular, Histones, Liver, Liver Neoplasms, Experimental, Nuclear Proteins, Placenta, Precancerous Conditions, Promoter Regions, Genetic, Proteins, Transcription Factors, Transcriptional Activation, Trans-Activators, Gene Expression Regulation, Neoplastic, Rats, Sprague-Dawley, Rats, Inbred LEC, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, MafK Transcription Factor, NF-E2-Related Factor 2, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review