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

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Open access
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
Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.0506070102

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Constitutive activation of Hif-1α in Vhl-deficient thymocytes results in a reduced calcium response following TCR cross-linking due to increased removal of calcium from the cytoplasm via Hif-1α-induced increases in SERCA2 calcium pumps.

    “Constitutive activation of Hif-1α in Vhl-deficient thymocytes also resulted in a reduced calcium response following TCR cross-linking that resulted from increased removal of calcium from the cytoplasm via Hif-1α-induced increases in SERCA2 calcium pumps [92].”

    From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [92]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 48 references couldn’t be matched to a known paper.

Research works printed but not linked: 47

  1. [1]Semenza, G. L. (2003) Annu. Rev. Med. 54, 17-28. [DOI] [PubMed] [Google Scholar]
  2. [2]Michiels, C. (2004) Am. J. Pathol. 164, 1875-1882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. [3]Kaelin, W. G., Jr. (2002) Genes Dev. 16, 1441-1445. [DOI] [PubMed] [Google Scholar]
  4. [4]Huang, L. E., Gu, J., Schau, M. & Bunn, H. F. (1998) Proc. Natl. Acad. Sci. USA 95, 7987-7992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. [5]Maxwell, P. H., Wiesener, M. S., Chang, G. W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R. & Ratcliffe, P. J. (1999) Nature 399, 271-275. [DOI] [PubMed] [Google Scholar]
  6. [6]Hale, L. P., Braun, R. D., Gwinn, W. M., Greer, P. K. & Dewhirst, M. W. (2002) Am. J. Physiol. 282, H1467-H1477. [DOI] [PubMed] [Google Scholar]
  7. [7]Caldwell, C. C., Kojima, H., Lukashev, D., Armstrong, J., Farber, M., Apasov, S. G. & Sitkovsky, M. V. (2001) J. Immunol. 167, 6140-6149. [DOI] [PubMed] [Google Scholar]
  8. [8]Braun, R. D., Lanzen, J. L., Snyder, S. A. & Dewhirst, M. W. (2001) Am. J. Physiol. 280, H2533-H2544. [DOI] [PubMed] [Google Scholar]
  9. [9]Makino, Y., Nakamura, H., Ikeda, E., Ohnuma, K., Yamauchi, K., Yabe, Y., Poellinger, L., Okada, Y., Morimoto, C. & Tanaka, H. (2003) J. Immunol. 171, 6534-6540. [DOI] [PubMed] [Google Scholar]
  10. [10]Distler, J. H., Wenger, R. H., Gassmann, M., Kurowska, M., Hirth, A., Gay, S. & Distler, O. (2004) Arthritis Rheum. 50, 10-23. [DOI] [PubMed] [Google Scholar]
  11. [11]Sitkovsky, M. V., Lukashev, D., Apasov, S., Kojima, H., Koshiba, M., Caldwell, C., Ohta, A. & Thiel, M. (2004) Annu. Rev. Immunol. 22, 657-682. [DOI] [PubMed] [Google Scholar]
  12. [12]Biju, M. P., Neumann, A. K., Bensinger, S. J., Johnson, R. S., Turka, L. A. & Haase, V. H. (2004) Mol. Cell. Biol. 24, 9038-9047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. [13]Schofield, C. J. & Ratcliffe, P. J. (2004) Nat. Rev. Mol. Cell. Biol. 5, 343-354. [DOI] [PubMed] [Google Scholar]
  14. [14]Semenza, G. L. (2001) Curr. Opin. Cell Biol. 13, 167-171. [DOI] [PubMed] [Google Scholar]
  15. [15]Wenger, R. H. (2002) FASEB J. 16, 1151-1162. [DOI] [PubMed] [Google Scholar]
  16. [16]Gnarra, J. R., Ward, J. M., Porter, F. D., Wagner, J. R., Devor, D. E., Grinberg, A., Emmert-Buck, M. R., Westphal, H., Klausner, R. D. & Linehan, W. M. (1997) Proc. Natl. Acad. Sci. USA 94, 9102-9107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. [17]Haase, V. H., Glickman, J. N., Socolovsky, M. & Jaenisch, R. (2001) Proc. Natl. Acad. Sci. USA 98, 1583-1588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. [18]Ryan, H. E., Poloni, M., McNulty, W., Elson, D., Gassmann, M., Arbeit, J. M. & Johnson, R. S. (2000) Cancer Res. 60, 4010-4015. [PubMed] [Google Scholar]
  19. [19]Lee, P. P., Fitzpatrick, D. R., Beard, C., Jessup, H. K., Lehar, S., Makar, K. W., Perez-Melgosa, M., Sweetser, M. T., Schlissel, M. S., Nguyen, S., et al. (2001) Immunity 15, 763-774. [DOI] [PubMed] [Google Scholar]
  20. [20]Freedman, B. D., Liu, Q. H., Somersan, S., Kotlikoff, M. I. & Punt, J. A. (1999) J. Exp. Med. 190, 943-952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. [21]Lewis, R. S. (2001) Annu. Rev. Immunol. 19, 497-521. [DOI] [PubMed] [Google Scholar]
  22. [22]Zweifach, A. & Lewis, R. S. (1993) Proc. Natl. Acad. Sci. USA 90, 6295-6299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [23]Putney, J. W., Jr., Broad, L. M., Braun, F. J., Lievremont, J. P. & Bird, G. S. (2001) J. Cell Sci. 114, 2223-2229. [DOI] [PubMed] [Google Scholar]
  24. [24]Bautista, D. M., Hoth, M. & Lewis, R. S. (2002) J. Physiol. 541, 877-894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [25]Gunter, T. E., Yule, D. I., Gunter, K. K., Eliseev, R. A. & Salter, J. D. (2004) FEBS Lett. 567, 96-102. [DOI] [PubMed] [Google Scholar]
  26. [26]Hoth, M., Fanger, C. M. & Lewis, R. S. (1997) J. Cell Biol. 137, 633-648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. [27]Oubrahim, H., Stadtman, E. R. & Chock, P. B. (2001) Proc. Natl. Acad. Sci. USA 98, 9505-9510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. [28]Friel, D. D. & Tsien, R. W. (1994) J. Neurosci. 14, 4007-4024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. [29]Smiley, S. T., Reers, M., Mottola-Hartshorn, C., Lin, M., Chen, A., Smith, T. W., Steele, G. D., Jr., & Chen, L. B. (1991) Proc. Natl. Acad. Sci. USA 88, 3671-3675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. [30]Bautista, D. M. & Lewis, R. S. (2004) J. Physiol. 556, 805-817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. [31]Launay, S., Bobe, R., Lacabaratz-Porret, C., Bredoux, R., Kovacs, T., Enouf, J. & Papp, B. (1997) J. Biol. Chem. 272, 10746-10750. [DOI] [PubMed] [Google Scholar]
  32. [32]Poch, E., Leach, S., Snape, S., Cacic, T., MacLennan, D. H. & Lytton, J. (1998) Am. J. Physiol. 275, C1449-C1458. [DOI] [PubMed] [Google Scholar]
  33. [33]Huang, Y., Hickey, R. P., Yeh, J. L., Liu, D., Dadak, A., Young, L. H., Johnson, R. S. & Giordano, F. J. (2004) FASEB J. 18, 1138-1140. [DOI] [PubMed] [Google Scholar]
  34. [34]Winslow, M. M., Neilson, J. R. & Crabtree, G. R. (2003) Curr. Opin. Immunol. 15, 299-307. [DOI] [PubMed] [Google Scholar]
  35. [35]Dolmetsch, R. E., Xu, K. & Lewis, R. S. (1998) Nature 392, 933-936. [DOI] [PubMed] [Google Scholar]
  36. [36]Bhakta, N. R., Oh, D. Y. & Lewis, R. S. (2005) Nat. Immunol. 6, 143-151. [DOI] [PubMed] [Google Scholar]
  37. [37]Dolmetsch, R. E. & Lewis, R. S. (1994) J. Gen. Physiol. 103, 365-388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. [38]Rizzuto, R., Pinton, P., Carrington, W., Fay, F. S., Fogarty, K. E., Lifshitz, L. M., Tuft, R. A. & Pozzan, T. (1998) Science 280, 1763-1766. [DOI] [PubMed] [Google Scholar]
  39. [39]Lukashev, D., Caldwell, C., Ohta, A., Chen, P. & Sitkovsky, M. (2001) J. Biol. Chem. 276, 48754-48763. [DOI] [PubMed] [Google Scholar]
  40. [40]Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. & Semenza, G. L. (2001) Mol. Cell. Biol. 21, 3995-4004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. [41]Jiang, B. H., Jiang, G., Zheng, J. Z., Lu, Z., Hunter, T. & Vogt, P. K. (2001) Cell Growth Differ. 12, 363-369. [PubMed] [Google Scholar]
  42. [42]Mekhail, K., Gunaratnam, L., Bonicalzi, M. E. & Lee, S. (2004) Nat. Cell. Biol. 6, 642-647. [DOI] [PubMed] [Google Scholar]
  43. [43]Atkuri, K. R., Herzenberg, L. A. & Herzenberg, L. A. (2005) Proc. Natl. Acad. Sci. USA 102, 3756-3759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. [44]Cramer, T., Yamanishi, Y., Clausen, B. E., Forster, I., Pawlinski, R., Mackman, N., Haase, V. H., Jaenisch, R., Corr, M., Nizet, V., et al. (2003) Cell 112, 645-657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. [45]Kojima, H., Gu, H., Nomura, S., Caldwell, C. C., Kobata, T., Carmeliet, P., Semenza, G. L. & Sitkovsky, M. V. (2002) Proc. Natl. Acad. Sci. USA 99, 2170-2174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. [46]Sitkovsky, M. & Lukashev, D. (2005) Nat. Rev. Immunol. 5, 712-721. [DOI] [PubMed] [Google Scholar]
  47. [47]Peyssonnaux, C., Datta, V., Cramer, T., Doedens, A., Theodorakis, E. A., Gallo, R. L., Hurtado-Ziola, N., Nizet, V. & Johnson, R. S. (2005) J. Clin. Invest. 115, 1806-1815. [DOI] [PMC free article] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Related

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
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review