Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1α Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP

Sang, Nianli; Fang, Jie; Srinivas, Vickram; Leshchinsky, Irene; Caro, Jaime

doi:10.1128/mcb.22.9.2984-2992.2002

Cited by 144Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentKruppel-like factors research

Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1α Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP

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Sang, Nianli, Fang, Jie, Srinivas, Vickram, Leshchinsky, Irene, Caro, Jaime·2002·Molecular and Cellular Biology

DOI 10.1128/mcb.22.9.2984-2992.2002PMC PMC133771

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Abstract

Hypoxia-inducible factor 1 complex (HIF-1) plays a pivotal role in oxygen homeostasis and adaptation to hypoxia. Its function is controlled by both the protein stability and the transactivation activity of its alpha subunit, HIF-1 alpha. Hydroxylation of at least two prolyl residues in the oxygen-dependent degradation domain of HIF-1 alpha regulates its interaction with the von Hippel-Lindau protein (VHL) that targets HIF-1 alpha for ubiquitination and proteasomal degradation. Several prolyl hydroxylases have been found to specifically hydroxylate HIF-1 alpha. In this report, we investigated possible roles of VHL and hydroxylases in the regulation of the transactivation activity of the C-terminal activating domain (CAD) of HIF-1 alpha. We demonstrate that regulation of the transactivation activity of HIF-1 alpha CAD also involves hydroxylase activity but does not require functional VHL. In addition, stimulation of the CAD activity by a hydroxylase inhibitor, hypoxia, and desferrioxamine was severely blocked by the adenoviral oncoprotein E1A but not by an E1A mutant defective in targeting p300/CBP. We further demonstrate that a hydroxylase inhibitor, hypoxia, and desferrioxamine promote the functional and physical interaction between HIF-1 alpha CAD and p300/CBP in vivo. Taken together, our data provide evidence that hypoxia-regulated stabilization and transcriptional stimulation of HIF-1 alpha function are regulated through partially overlapping but distinguishable pathways.

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Regulation of the CAD by hydroxylation does not appear to require pVHL.
“although regulation of the CAD by hydroxylation does not appear to require pVHL (Sang et al. 2002).”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Sang et al. 2002

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Pereira, T., Zheng, X., Ruas, J. L., Tanimoto, K., & Poellinger, L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209297200 · Cited by 57 · see citing works
Mechanism of regulation of the hypoxia‐inducible factor‐1α by the von Hippel‐Lindau tumor suppressor protein
Tanimoto, K., Makino, Y., Pereira, T., & Poellinger, L. (2000) · The EMBO Journal · doi:10.1093/emboj/19.16.4298 · Cited by 928 · see citing works

Authors: Sang, N., Fang, J., Srinivas, V., Leshchinsky, I., & Caro, J.
Affiliations: Thomas Jefferson University (US)
Corresponding author: Caro, Jaime
ORCID: Sang, Nianli
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2002-05-01
Volume: 22
Issue: 9
Pages: 2984-2992
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.22.9.2984-2992.2002
PMC: PMC133771
OpenAlex: W2121895466
Cited by: 143
References: 55
Citations by year: 2025: 2 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 8 · 2014: 3 · 2013: 5 · 2012: 4
FWCI: 6.64
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Heart Association
Fudan University
Huashan Hospital
National Institutes of Health
National Heart, Lung, and Blood Institute (T32HL007821)
National Cancer Institute (R01CA089212, R01CA89212-02)
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 › Kruppel-like factors research
Keywords: hypoxia-inducible factor-1α, prolyl hydroxylase, von Hippel-Lindau protein, CBP/p300, deferoxamine, hypoxia, oxygen homeostasis, transcriptional regulation, protein stability
MeSH terms: Hypoxia, Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Cell Line, Deferoxamine, Dihydroorotase, DNA-Binding Proteins, HeLa Cells, Humans, Mixed Function Oxygenases, Hydroxylation, Ligases, Multienzyme Complexes, Nuclear Proteins, Protein Binding, Transcription Factors, Blotting, Western, Transcriptional Activation, Trans-Activators, Adenovirus E1A Proteins, Protein Isoforms, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit

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Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1α Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP

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