Cited by 386Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentUbiquitin and proteasome pathways

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Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-α-prolyl-4-hydroxylases

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MARXSEN, Jan H., STENGEL, Petra, DOEGE, Kathrin, HEIKKINEN, Pekka, JOKILEHTO, Terhi, WAGNER, Thomas, JELKMANN, Wolfgang, JAAKKOLA, Panu, METZEN, Eric·2004·Biochemical Journal

DOI 10.1042/bj20040620PMC PMC1133886

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Abstract

An important regulator involved in oxygen-dependent gene expression is the transcription factor HIF (hypoxia-inducible factor), which is composed of an oxygen-sensitive α-subunit (HIF-1α or HIF-2α) and a constitutively expressed β-subunit. In normoxia, HIF-1α is destabilized by post-translational hydroxylation of Pro-564 and Pro-402 by a family of oxygen-sensitive dioxygenases. The three HIF-modifying human enzymes have been termed prolyl hydroxylase domain containing proteins (PHD1, PHD2 and PHD3). Prolyl hydroxylation leads to pVHL (von-Hippel-Lindau protein)-dependent ubiquitination and rapid proteasomal degradation of HIF-1α. In the present study, we report that human PHD2 and PHD3 are induced by hypoxia in primary and transformed cell lines. In the human osteosarcoma cell line, U2OS, selective suppression of HIF-1α expression by RNA interference resulted in a complete loss of hypoxic induction of PHD2 and PHD3. Induction of PHD2 by hypoxia was lost in pVHL-deficient RCC4 cells. These results suggest that hypoxic induction of PHD2 and PHD3 is critically dependent on HIF-α. Using a VHL capture assay, we demonstrate that HIF-α prolyl-4-hydroxylase capacity of cytoplasmic and nuclear protein extracts was enhanced by prolonged exposure to hypoxia. Degradation of HIF-1α after reoxygenation was accelerated, which demonstrates functional relevance of the present results. We propose a direct, negative regulatory mechanism, which limits accumulation of HIF-1α in hypoxia and leads to accelerated degradation on reoxygenation after long-term hypoxia.

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Authors: MARXSEN, J. H., STENGEL, P., DOEGE, K., HEIKKINEN, P., JOKILEHTO, T., WAGNER, T., JELKMANN, W., JAAKKOLA, P., & METZEN, E.
Affiliations: University of Lübeck (DE)
Åbo Akademi University (FI)
Corresponding author: WAGNER, Thomas
ORCID: JAAKKOLA, Panu
METZEN, Eric
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 2004-07-27
Volume: 381
Issue: 3
Pages: 761-767
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bj20040620
PMC: PMC1133886
OpenAlex: W2062805420
Semantic Scholar: 78f44730e6dafeb8230f0ee75c3e637a1b6fd07a
Cited by: 386
References: 36
Citations by year: 2026: 14 · 2025: 26 · 2024: 26 · 2023: 17 · 2022: 15 · 2021: 20 · 2020: 10 · 2019: 13 · 2018: 12 · 2017: 18 · 2016: 12 · 2015: 20 · 2014: 16 · 2013: 17 · 2012: 12
FWCI: 8.97
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Biochemical Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft (SFB367)
Academy of Finland
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: HIF-1, HIF-1α, prolyl 4-hydroxylase, PHD2, PHD3, HIF-1α degradation, hypoxia, von Hippel-Lindau protein, ubiquitination, proteasomal degradation, reoxygenation, oxygen sensing, transcriptional regulation, osteosarcoma cells, RNA interference
MeSH terms: Hypoxia, Bone Neoplasms, Cell Line, DNA-Binding Proteins, Enzyme Induction, Epithelial Cells, Half-Life, Carcinoma, Hepatocellular, Humans, Hydroxylation, Kidney Neoplasms, Kidney Tubules, Proximal, Liver Neoplasms, Nuclear Proteins, Oxygen, Procollagen-Proline Dioxygenase, RNA, Messenger, Osteosarcoma, Transcription Factors, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Immediate-Early Proteins, Adenocarcinoma, Clear Cell, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Dioxygenases, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases

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Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-α-prolyl-4-hydroxylases

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