HIF-independent role of prolyl hydroxylases in the cellular response to amino acids
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Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are α-ketoglutarate (αKG)-dependent dioxygenases that function as cellular oxygen sensors. However, PHD activity also depends on factors other than oxygen, especially αKG, a key metabolic compound closely linked to amino-acid metabolism. We examined the connection between amino-acid availability and PHD activity. We found that amino-acid starvation leads to αKG depletion and to PHD inactivation but not to HIF stabilization. Furthermore, pharmacologic or genetic inhibition of PHDs induced autophagy and prevented mammalian target of rapamycin complex 1 (mTORC1) activation by amino acids in a HIF-independent manner. Therefore, PHDs sense not only oxygen but also respond to amino acids, constituting a broad intracellular nutrient-sensing network.
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α-KG induces mTORC1 activation by enhancing GTP loading of RagB in a PHD-dependent manner, promoting cell growth.
“α-KG induces mTORC1 activation by enhancing GTP loading of the RagB protein in a PHD-dependent manner, thus promoting cell growth160,161.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [161]
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- Authors
- Durán, R. V., MacKenzie, E. D., Boulahbel, H., Frezza, C., Heiserich, L., Tardito, S., Bussolati, O., Rocha, S., Hall, M. N., & Gottlieb, E.
- Affiliations
- University of Basel (CH)
- Cancer Research UK (GB)
- University of Parma (IT)
- University of Dundee (GB)
- Corresponding author
- Gottlieb, E
- Venue
- Oncogene
- Published
- 2012-10-22
- Volume
- 32
- Issue
- 38
- Pages
- 4549-4556
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3787797
- OpenAlex
- W2127584960
- Cited by
- 139
- References
- 38
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 6 · 2023: 10 · 2022: 9 · 2021: 7 · 2020: 20 · 2019: 13 · 2018: 9 · 2017: 10 · 2016: 12 · 2015: 10 · 2014: 14 · 2013: 4 · 2012: 1
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Oncogene (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- edoc (University of Basel) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- edoc (University of Basel)
- Funders
- National Science Foundation
- Wellcome Trust (097945)
- Cancer Research UK (A12918, 12918)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Medical Research Council (MC_UU_12022/6)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- prolyl hydroxylase, hypoxia-inducible factor, alpha-ketoglutarate, amino acid sensing, amino acid starvation, autophagy, mTORC1, nutrient sensing, oxygen sensing
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acids, Animals, Cell Line, Enzyme Activation, Humans, Ketoglutaric Acids, Models, Biological, Procollagen-Proline Dioxygenase, Multiprotein Complexes, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases
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