CoChat
Sign Up
Cited by 2,476Cancer, Hypoxia, and MetabolismDevelopmental Biology and Gene RegulationAngiogenesis and VEGF in Cancer

Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α

Open access
Iyer, Narayan V., Kotch, Lori E., Agani, Faton, Leung, Sandra W., Laughner, Erik, Wenger, Roland H., Gassmann, Max, Gearhart, John D. +3 more·1998·Genes & Development
DOI 10.1101/gad.12.2.149PMC PMC316445
Open this paper in CoChat — free accountOpen PDF

Abstract

Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, stroke, and other major causes of mortality. Hypoxia-inducible factor 1 (HIF-1) is the only known mammalian transcription factor expressed uniquely in response to physiologically relevant levels of hypoxia. We now report that in Hif1a −/− embryonic stem cells that did not express the O 2 -regulated HIF-1α subunit, levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. Vascular endothelial growth factor mRNA expression was also markedly decreased in hypoxic Hif1a −/− embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1α resulted in developmental arrest and lethality by E11 of Hif1a −/− embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1a +/+ embryos, HIF-1α expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1a −/− embryos. These results demonstrate that HIF-1α is a master regulator of cellular and developmental O 2 homeostasis.

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 · 10.1101/gad.12.2.149

Cites

63 of 63 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?

  • Hypoxia promotes aerobic glycolysis by increasing both glucose uptake and expression of glycolytic enzymes.

    “Hypoxia promotes aerobic glycolysis by increasing both glucose uptake and expression of glycolytic enzymes (Iyer et al., 1998).”

    From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Iyer et al., 1998

    In the section on O₂-regulated gene expression in ES cells, the paper reports that hypoxia induced many glucose-transporter and glycolytic-enzyme mRNAs in Hep3B cells. It did not report a corresponding increase in glucose uptake, and hypoxia had little effect on those mRNAs in wild-type ES cells. On p. 155, it discusses aerobic glycolysis in nonhypoxic cells, not as an outcome shown to be promoted by hypoxia. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Most glycolytic enzymes are transcriptionally regulated by HIF-1a.

    “Most glycolytic enzymes are transcriptionally regulated by the hypoxia-inducible transcriptional factor HIF-1a (40).”

    From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [40]

  • In an analysis of 15 glucose transporter and glycolytic genes in embryonic stem cells lacking HIF1a, only PGM and GPI were exceptions.

    “Interestingly, PGM and GPI were the only exceptions noted in a study of 15 glucose transporter and glycolytic genes in HIF1a null embryonic stem cells (40).”

    From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [40]

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

Research works printed but not linked: 10

  1. Au su bel, F.M ., R. Bren t , R.E. Kin gst on , D .D . M oore, J.G . Seidm an , J.A. Sm it h , K. St ru h l, L.M . Albrigh t , D . C oen , M .A. Vark i, an d K. Jan ssen . 1994. C u rren t prot ocols in m olecu lar b iology . Joh n Wiley an d Son s, N ew York , N Y. Ben jam in , L.E. an d E. Kesh et . 1997. C on dit ion al sw it ch in g of vascu lar en dot h elial grow t h fact or (VEG F) expression in t u - m ors: In du ct ion of en dot h elial cell sh eddin g an d regression of h em an gioblast om a-lik e vessels by VEG F w it h draw al. Proc. N at l. A cad . Sci. 94: 8761-8766.
  2. Bradley, A. 1987. Produ ct ion an d an alysis of ch im aeric m ice. In T erat ocarcin om as an d em b ry on ic st em cells: A pract ical approach , 1st ed. (ed. E.J. Robert son ), pp. 113-152. IRL Press, O xford, U K. C arm eliet , P., V. Ferreira, G . Breier, S. Pollefeyt , L. Kieck en s, M . G ert esen st ein , M . Fah rig, A. Van den h oeck , K. H arpal, C . Eb- erh ardt , C . D eclercq, J. Paw lin g, L. M oon s, D . C ollen , W. Risau , an d A. N agy. 1996. Abn orm al blood vessel develop- m en t an d let h alit y in em bryos lack in g a sin gle VEG F allele. N at u re 380: 435-439.
  3. C arroll, R.C ., J.F. Ash , P.K. Vogt , an d S.J. Sin ger. 1978. Rever- sion of t ran sform ed glycolysis t o n orm al by in h ibit ion of prot ein syn t h esis in rat k idn ey cells in fect ed w it h t em pera- t u re-sen sit ive m u t an t of Rou s sarcom a viru s. Proc. N at l. A cad . Sci. 75: 5015-5019.
  4. D olw ick , K.M ., H .I. Sw an son , an d C .A. Bradfield. 1993. In vit ro an alysis of Ah recept or dom ain s in volved in ligan d-act ivat ed t ran script ion . Proc. N at l. A cad . Sci. 90: 8566-8570.
  5. Em a, M ., S. T aya, N . Yok ot an i, K. Sogaw a, Y. M at su da, an d Y. Fu jii-Ku riyam a. 1997. A n ovel bH LH -PAS fact or w it h close sequ en ce sim ilarit y t o h ypoxia-in du cible fact or 1␣ regu lat es V EG F expression an d is pot en t ially in volved in lu n g an d vascu lar developm en t . Proc. N at l. A cad . Sci. 94: 4273-4278.
  6. G assm an n , M ., J. Fan drey, S. Bich et , M . Wart en berg, H .H . M art i, C . Bau er, R.H . Wen ger, an d H . Ack er. 1996. O xygen su pply an d oxygen -depen den t gen e expression in differen t i- at in g em bryon ic st em cells. Proc. N at l. A cad . Sci. 93: 2867- 2872.
  7. H ogan , B., R. Beddin gt on , F. C ost an t in i, an d E. Lacy. 1994. M a- n ipu lat in g t h e m ou se em b ry o: A lab orat ory m an u al. C old Sprin g H arbor Laborat ory Press, C old Sprin g H arbor, N Y. H ogen esch , J.B., W.K. C h an , V.H . Jack iw , R.C . Brow n , Y.-Z . G u , G .H . Perdew , an d C .A. Bradfield. 1997. C h aract erizat ion of a su bset of t h e basic-h elix-loop-h elix-PAS su perfam ily t h at in - t eract s w it h com pon en t s of t h e dioxin sign allin g pat h w ay. J. Biol. C h em . 272: 8581-8593.
  8. M art in , C ., A.Y. Yu , B.-H . Jian g, L. D avis, D . Kim berly, A.R. H oh im er, an d G .L. Sem en za. 1997. C ardiac h ypert roph y in ch ron ically an em ic sh eep: In creased vascu larizat ion is asso- ciat ed w it h in creased m yocardial expression of vascu lar en - dot h elial grow t h fact or an d h ypoxia-in du cible fact or 1. A m . J. O b st et . G y n ecol. (in press).
  9. Robert son , E.J. 1987. Em bryo-derived st em cell lin es. In T era- t ocarcin om as an d em b ry on ic st em cells: A pract ical ap- proach , 1st ed. (ed. E.J. Robert son ), pp. 71-112. IRL Press, O xford, U K. Salceda, S., I. Beck , an d J. C aro. 1996. Absolu t e requ irem en t of aryl h ydrocarbon recept or n u clear t ran slocat or prot ein for gen e act ivat ion by h ypoxia. A rch . Bioch em . Bioph y s. 334: 389-394.
  10. Wan g, G .L., B.-H . Jian g, E.A. Ru e, an d G .L. Sem en za. 1995. H yp- oxia-in du cible fact or 1 is a basic-h elix-loop-h elix-PAS h et - erodim er regu lat ed by cellu lar O 2 t en sion . Proc. N at l. A cad . Sci. 92: 5510-5514.

Cited by

Sorted by citations

Related

Authors
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., & Semenza, G. L.
Affiliations
Johns Hopkins University (US)
Corresponding author
Semenza, Gregg L.
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
1998-01-15
Volume
12
Issue
2
Pages
149-162
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.12.2.149
PMC
PMC316445
OpenAlex
W2098972920
Cited by
2,476
References
61
Citations by year
2026: 34 · 2025: 49 · 2024: 69 · 2023: 69 · 2022: 98 · 2021: 99 · 2020: 92 · 2019: 78 · 2018: 86 · 2017: 84 · 2016: 87 · 2015: 94 · 2014: 93 · 2013: 100 · 2012: 90
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • National Institutes of Health (5r01dk039869-16)
  • National Heart, Lung, and Blood Institute (R01HL55338, R01HL055338)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK39869)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
hypoxia-inducible factor-1α, oxygen homeostasis, hypoxia, embryonic stem cells, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, embryoid bodies, neural tube defects, cardiovascular anomalies, developmental arrest, transcriptional regulation
MeSH terms
Animals, Blood Vessels, Cell Division, Cells, Cultured, DNA-Binding Proteins, Embryo, Mammalian, Homeostasis, Immunohistochemistry, Lymphokines, Mice, Inbred C57BL, Nuclear Proteins, Oxygen, RNA, Messenger, Stem Cells, Time Factors, Transcription Factors, Immunoblotting, Endothelial Growth Factors, Mice, Knockout, Cell Respiration, Platelet Endothelial Cell Adhesion Molecule-1, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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