Cited by 234Cancer, Hypoxia, and MetabolismHeat shock proteins researchUbiquitin and proteasome pathways

Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but not HIF-2α

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Luo, Weibo, Zhong, Jun, Chang, Ryan, Hu, Hongxia, Pandey, Akhilesh, Semenza, Gregg L.·2010·Journal of Biological Chemistry

Abstract

Hypoxia-inducible factors (HIFs) are transcription factors that mediate adaptive responses to reduced oxygen availability. HIF-alpha subunits are stabilized under conditions of acute hypoxia. However, prolonged hypoxia leads to decay of HIF-1alpha but not HIF-2alpha protein levels by unknown mechanisms. Here, we identify Hsp70 and CHIP (carboxyl terminus of Hsc70-interacting protein) as HIF-1alpha-interacting proteins. Hsp70, through recruiting the ubiquitin ligase CHIP, promotes the ubiquitination and proteasomal degradation of HIF-1alpha but not HIF-2alpha, thereby inhibiting HIF-1-dependent gene expression. Disruption of Hsp70-CHIP interaction blocks HIF-1alpha degradation mediated by Hsp70 and CHIP. Inhibition of Hsp70 or CHIP synthesis by RNA interference increases protein levels of HIF-1alpha but not HIF-2alpha and attenuates the decay of HIF-1alpha levels during prolonged hypoxia. Thus, Hsp70- and CHIP-dependent ubiquitination represents a molecular mechanism by which prolonged hypoxia selectively reduces the levels of HIF-1alpha but not HIF-2alpha protein.

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  • PKM2 preferentially bound to GST-HIF-1α (531-826) fusion protein compared to GST alone in a SILAC-based proteomic screen.

    “A stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic screen (Luo et al., 2010) revealed that PKM2 preferentially bound to a GST-HIF-1α (531–826) fusion protein containing amino acid residues 531–826 of HIF-1α as compared to GST alone (Figure 2A), suggesting that PKM2 is a novel HIF-1α-interacting protein.”

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  1. Wang, G. L., Jiang, B. H., Rue, E. A., and Semenza, G. L. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 5510 -5514
  2. Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., and Fujii- Kuriyama, Y. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 4273-4278
  3. Arany, Z., Huang, L. E., Eckner, R., Bhattacharya, S., Jiang, C., Goldberg, M. A., Bunn, H. F., and Livingston, D. M. (1996) Proc. Natl. Acad. Sci.
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Authors
Luo, W., Zhong, J., Chang, R., Hu, H., Pandey, A., & Semenza, G. L.
Affiliations
Johns Hopkins University (US)
Corresponding author
Semenza, Gregg L.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-02
Volume
285
Issue
6
Pages
3651-3663
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2022643257
Cited by
232
References
39
Citations by year
2026: 5 · 2025: 9 · 2024: 15 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 16 · 2019: 18 · 2018: 10 · 2017: 18 · 2016: 15 · 2015: 22 · 2014: 11 · 2013: 19 · 2012: 15
FWCI
4.24
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Johns Hopkins University
  • National Institutes of Health (n01hv28180-13-0-0, RR020839)
  • National Heart, Lung, and Blood Institute (N01 HV-28180, N01 HV028180)
  • National Center for Research Resources (U54RR020839)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
HSP70, CHIP, HIF-1α, HIF-2α, hypoxia-inducible factor, ubiquitination, proteasomal degradation, protein stability, prolonged hypoxia, ubiquitin ligase
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Cell Line, Humans, Mutation, Protein Binding, Transfection, Immunoblotting, Cell Hypoxia, HSP70 Heat-Shock Proteins, RNA Interference, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteasome Endopeptidase Complex, Immunoprecipitation, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination

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