Cited by 457Erythropoietin and Anemia TreatmentCancer, Hypoxia, and MetabolismHemoglobinopathies and Related Disorders

Acute postnatal ablation of Hif-2 α results in anemia

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Gruber, Michaela, Hu, Cheng-Jun, Johnson, Randall S., Brown, Eric J., Keith, Brian, Simon, M. Celeste·2007·Proceedings of the National Academy of Sciences

Abstract

Adaptive transcriptional responses to oxygen deprivation (hypoxia) are mediated by the hypoxia-inducible factors (HIFs), heterodimeric transcription factors composed of two basic helix-loop-helix-PAS family proteins. The transcriptional activity of HIF is determined by the hypoxic stabilization of the HIF-alpha proteins. HIF-1alpha and HIF-2alpha exhibit high sequence homology but have different mRNA expression patterns; HIF-1alpha is expressed ubiquitously whereas HIF-2alpha expression is more restricted to certain tissues, e.g., the endothelium, lung, brain, and neural crest derivatives. Germ-line deletion of either HIF subunit is embryonic lethal with unique features suggesting important roles for both HIF-alpha isoforms. Global deletion of Hif-2alpha results in distinct phenotypes depending on the mouse strain used for the mutation, clearly demonstrating an important role for HIF-2alpha in mouse development. The function of HIF-2alpha in adult life, however, remains incompletely understood. In this study, we describe the generation of a conditional murine Hif-2alpha allele and the effect of its acute postnatal ablation. Under very stringent conditions, we ablate Hif-2alpha after birth and compare the effect of acute global deletion of Hif-2alpha and Hif-1alpha. Our results demonstrate that HIF-2alpha plays a critical role in adult erythropoiesis, with acute deletion leading to anemia. Furthermore, although HIF-1alpha was first purified and cloned based on its affinity for the human erythropoietin (EPO) 3' enhancer hypoxia response element (HRE) and regulates Epo expression during mouse embryogenesis, HIF-2alpha is the critical alpha isoform regulating Epo under physiologic and stress conditions in adults.

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Crossref · 10.1073/pnas.0608382104

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  • Acute postnatal global ablation of HIF-2α but not HIF-1α resulted in anemia responsive to recombinant EPO.

    “Acute postnatal global ablation of HIF-2α but not of HIF-1α, resulted in anemia, which, similar to HIF-2α germ line inactivation, was responsive to treatment with recombinant EPO. 71”

    From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [71]

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  1. [27]Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS. Cancer Res. 2000;60:4010–4015. [PubMed] [Google Scholar]

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Authors
Gruber, M., Hu, C.-J., Johnson, R. S., Brown, E. J., Keith, B., & Simon, M. C.
Affiliations
  • University of Vienna (AT)
  • Abramson Cancer Center (US)
  • University of California San Diego (US)
  • Howard Hughes Medical Institute (US)
Venue
Proceedings of the National Academy of Sciences
Published
2007-02-13
Volume
104
Issue
7
Pages
2301-2306
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2044257922
Cited by
457
References
38
Citations by year
2026: 10 · 2025: 14 · 2024: 37 · 2023: 13 · 2022: 20 · 2021: 19 · 2020: 26 · 2019: 24 · 2018: 24 · 2017: 14 · 2016: 27 · 2015: 26 · 2014: 22 · 2013: 22 · 2012: 24
FWCI
23.64
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancer Research Institute
  • Boehringer Ingelheim Fonds
  • National Institutes of Health
  • U.S. Public Health Service (66310)
  • Abramson Family Cancer Research Institute
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
Keywords
HIF-2α, HIF-1α, hypoxia-inducible factor, anemia, erythropoiesis, erythropoietin, hypoxia response element, conditional knockout mice, oxygen deprivation, transcriptional regulation
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Anemia, Animals, Hypoxia, Erythropoiesis, Erythropoietin, Gene Expression Regulation, Phenotype, Stress, Physiological, Mice, Knockout, Protein Isoforms, Response Elements, Mice, Basic Helix-Loop-Helix Proteins

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