AMP-activated Protein Kinase Regulates HNF4α Transcriptional Activity by Inhibiting Dimer Formation and Decreasing Protein Stability
Open accessAbstract
AMP-activated protein kinase (AMPK) is the central component of a cellular signaling system that regulates multiple metabolic enzymes and pathways in response to reduced intracellular energy levels. The transcription factor hepatic nuclear factor 4alpha (HNF4alpha) is an orphan nuclear receptor that regulates the expression of genes involved in energy metabolism in the liver, intestine, and endocrine pancreas. Inheritance of a single null allele of HNF4alpha causes diabetes in humans. Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. These results demonstrate that HNF4alpha is a downstream target of AMPK and raise the possibility that one of the effects of AMPK activation is reduced expression of HNF4alpha target genes.
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A similar reduction was seen upon addition of YAP S94A mutant.
“A similar reduction was also seen upon addition of YAP S94A mutant (Hong et al., 2003).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Hong et al., 2003
Cites
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The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
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AMPK and PPARδ Agonists Are Exercise Mimetics
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Hardie, D. G. (2003) · Endocrinology · doi:10.1210/en.2003-0982 · Cited by 994 · see citing works
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HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer
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Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation
Alder, O., Cullum, R., Lee, S., Kan, A. C., Wei, W., Yi, Y., Garside, V. C., Bilenky, M., Griffith, M., Morrissy, A. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.046 · Cited by 113 · see citing works
“A similar reduction was also seen upon addition of YAP S94A mutant (Hong et al., 2003).”
BackgroundMethodAatsinki, S., Buler, M., Salomäki, H., Koulu, M., Pavek, P., & Hakkola, J. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12585 · Cited by 85 · see citing works
Thakur, A., Wong, J. C. H., Wang, E. Y., Lotto, J., Kim, D., Cheng, J., Mingay, M., Cullum, R., Moudgil, V., Ahmed, N., et al. (2019) · Hepatology · doi:10.1002/hep.30631 · Cited by 75 · see citing works
“HEK293T cells were transfected with an HNF4A expression vector(32) and hemagglutinin-tagged TET3 vector (Addgene #49446) alone and in combination using polyethylenimine.”
MethodLiu, F., Peng, Y., Qian, H., Xiao, M. C., Ding, C. H., Zhang, X., & Xie, W. F. (2024) · Journal of Digestive Diseases · doi:10.1111/1751-2980.13272 · Cited by 5 · see citing works
- Authors
- Hong, Y. H., Varanasi, U. S., Yang, W., & Leff, T.
- Affiliations
- Pfizer (United States) (US)
- Wayne State University (US)
- Corresponding author
- Leff, Todd
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-07
- Volume
- 278
- Issue
- 30
- Pages
- 27495-27501
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2006227722
- Cited by
- 220
- References
- 1
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 11 · 2023: 6 · 2022: 13 · 2021: 5 · 2020: 11 · 2019: 6 · 2017: 16 · 2016: 6 · 2015: 9 · 2014: 15 · 2013: 8 · 2012: 8
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- AMPK, HNF4α, transcriptional repression, protein phosphorylation, homodimerization, protein stability, protein degradation, orphan nuclear receptor, energy metabolism, diabetes mellitus
- MeSH terms
- Alleles, Amino Acid Sequence, Animals, Binding Sites, DNA-Binding Proteins, Genetic Vectors, Cricetinae, Molecular Sequence Data, Multienzyme Complexes, Mutation, Phosphoproteins, Phosphorylation, Plasmids, Promoter Regions, Genetic, Serine, Time Factors, Transcription Factors, Transcription, Genetic, Transfection, Blotting, Western, Gene Expression Regulation, Enzymologic, CHO Cells, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Genes, Reporter, Dimerization, Hepatocyte Nuclear Factor 4, AMP-Activated Protein Kinases
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