Cited by 120Cancer, Hypoxia, and MetabolismT-cell and B-cell ImmunologySignaling Pathways in Disease

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Hypoxia inducible factor 1α regulates T cell receptor signal transduction

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Neumann, Aaron K., Yang, Jaeseok, Biju, Mangat P., Joseph, Suresh K., Johnson, Randall S., Haase, Volker H., Freedman, Bruce D., Turka, Laurence A.·2005·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0506070102PMC PMC1287984

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Abstract

Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1α. Here, we have examined the effect of Hif-1α, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel–Lindau protein) directs the proteolysis of Hif-1α under “normoxic” conditions, we achieved constitutive stabilization of Hif-1α through thymic deletion of Vhlh and reversed Hif-1α stabilization with double deletion of Vhlh and Hif-1 α. We found that constitutive activity of Hif-1α resulted in diminished Ca 2+ response upon TCR crosslinking despite equivalent activation of phospholipase C γ1 , normal intracellular Ca 2+ stores, and normal entry of Ca 2+ across the plasma membrane. Altered Ca 2+ response was instead due to accelerated removal of Ca 2+ from the cytoplasm into intracellular compartments, which occurred in association with Hif-1α-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic/endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1α, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.

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Authors: Neumann, A. K., Yang, J., Biju, M. P., Joseph, S. K., Johnson, R. S., Haase, V. H., Freedman, B. D., & Turka, L. A.
Affiliations: Thomas Jefferson University (US)
Department of Medicine and Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104; Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107; Division of Biological Sciences, University of California, San Diego, CA 92093; and Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
ORCID: Neumann, Aaron K.
Yang, Jaeseok
Joseph, Suresh K.
Johnson, Randall S.
Haase, Volker H.
Freedman, Bruce D.
Turka, Laurence A.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2005-11-14
Volume: 102
Issue: 47
Pages: 17071-17076
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0506070102
PMC: PMC1287984
OpenAlex: W2071062200
Cited by: 120
References: 48
Citations by year: 2026: 2 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 6 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 3 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 5 · 2012: 7
FWCI: 2.67
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Heart Association
National Institutes of Health
National Cancer Institute (R01CA100787)
National Institute of Allergy and Infectious Diseases (AI 43626, R01AI043626, R21AI043626, R01AI060921)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: hypoxia-inducible factor-1α, T cell receptor signaling, thymocytes, calcium signaling, von Hippel-Lindau protein, HIF-1α stabilization, SERCA2, calcium pump, phospholipase C-gamma1, hypoxia
MeSH terms: Calcium-Transporting ATPases, Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Mitochondria, Receptors, Antigen, T-Cell, Thymus Gland, Down-Regulation, Mice, Knockout, Calcium Signaling, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Sarcoplasmic Reticulum Calcium-Transporting ATPases

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