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Cited by 909Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerErythropoietin and Anemia Treatment

HIF-1 and human disease: one highly involved factor

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Semenza, Gregg L.·2000·Genes & Development
DOI 10.1101/gad.14.16.1983
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Abstract

Oxygen homeostasis represents an important organizing principle for human development and physiology. The essential requirement for oxidative phosphorylation to generate ATP is balanced by the risk of oxidative damage to cellular lipids, nucleic acids, and proteins. As a result, cellular and systemic O2 concentrations are tightly regulated via shortand long-acting response pathways that affect the activity and expression of a multitude of cellular proteins (for review, see Semenza 1999a). This delicate balance is disrupted in heart disease, cancer, cerebrovascular disease, and chronic obstructive pulmonary disease, which represent the most common causes of mortality and account for two-thirds of all deaths in the U.S. (Greenlee 2000). Appreciation of the fundamental importance of oxygen homeostasis for development, physiology, and disease pathophysiology is growing but still incomplete. Knowledge acquisition is presently exponential when one includes areas, such as the role of angiogenesis in ischemic or neoplastic disease, in which investigators are studying oxygen homeostasis even though they may not interpret their studies within this broad physiological context. Vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis (for review, see Ferrara and Davis-Smyth 1997; Ferrara 1999). The regulation of VEGF expression illustrates how reduced O2 availability (hypoxia) can elicit physiological responses via multiple molecular mechanisms. VEGF expression is induced when most cell types are subjected to hypoxia, thus providing a mechanism by which tissue perfusion can be optimized to demand. Steady state levels of VEGF mRNA increase in hypoxic cells as a result of increased production (transcriptional activation) and decreased destruction (mRNA stabilization). Whereas overall protein synthesis is inhibited in response to hypoxia, VEGF mRNA is efficiently translated into protein by use of an internal ribosome entry site (Stein et al. 1998). Finally, expression of the VEGF receptor FLT-1 is also induced when endothelial cells are exposed to hypoxia (Gerber et al. 1997). The essential first step in this process, transcriptional activation, is mediated by the binding of hypoxia-inducible factor 1 (HIF-1) to a cis-acting hypoxia-response element located 1 kb 5 to the transcriptional start site of the human VEGF gene (Forsythe et al. 1996). HIF-1 is a basic helix–loop–helix PAS protein consisting of HIF-1 and HIF-1 subunits (Wang and Semenza 1995; Wang et al. 1995). HIF-1 expression and HIF-1 transcriptional activity are precisely regulated by cellular O2 concentration (for review, see Semenza 1999b, 2000a; Wenger 2000). The molecular mechanisms of sensing and signal transduction by which changes in O2 concentration result in changes in HIF-1 activity are poorly understood, but recent data suggest that the O2 signal is converted to a redox signal (Chandel et al. 2000; Haddad et al. 2000) that may trigger a kinase cascade and/or regulate HIF-1 directly (for review, see Semenza 1999a,b; Chandel and Schumacker 2000). The regulation of HIF-1 activity occurs at multiple levels. Whereas HIF-1 mRNA is constitutively expressed in tissue culture cells, it is markedly induced by hypoxia or ischemia in vivo (Yu et al. 1998; Bergeron et al. 1999). HIF-1 protein expression is negatively regulated in nonhypoxic cells by ubiquitination and proteasomal degradation (Salceda and Caro 1997; Huang et al. 1998; Kallio et al. 1999). Under hypoxic conditions, HIF-1 protein levels increase dramatically and the fraction that is ubiquitinated decreases (Sutter et al. 2000). Nuclear localization of HIF-1 may also be induced by hypoxia (Kallio et al. 1998). The carboxy-terminal half of HIF-1 contains two transactivation domains that are also negatively regulated under nonhypoxic conditions (Jiang et al. 1997b; Pugh et al. 1997). The interaction of these domains with the coactivators CBP, p300, SRC-1, and TIF2 is regulated by the cellular O2 concentration and redox state (Kallio et al. 1998; Ema et al. 1999; Carrero et al. 2000). Finally, species–specific alternative splicing of human and mouse HIF-1 RNA has also been reported (Wenger et al. 1997; Iyer et al. 1998b; Gothie et al. 2000). Hypoxia results in the rapid accumulation of HIF-1 in the nucleus (Wang et al. 1995) where it dimerizes with HIF-1 and binds to the core DNA sequence 5 -RCGTG3 (Semenza 2000a), leading to the transcriptional activation of VEGF and several dozen other known target genes (Table 1). HIF-1 and HIF-1 expression are required for embryonic survival in mice (Kozak et al. 1997; Maltepe et al. 1997; Iyer et al. 1998a; Ryan et al. 1998; 1E-MAIL gsemenza@jhmi.edu; FAX (410) 955-0484.

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  • Activated HIF-1 plays a crucial role in adaptive responses of tumor cells to changes in oxygen through transcriptional activation of over 100 downstream genes.

    “Activated HIF-1 plays a crucial role in adaptive responses of the tumor cells to changes in oxygen through transcriptional activation of over 100 downstream genes which regulate vital biological processes required for tumor survival and progression.”

    From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [1]

    The section on HIF-1 regulation says hypoxia leads to transcriptional activation of VEGF and several dozen other known target genes, not over 100. The section on tumor biology links those target genes to metabolic adaptation, angiogenesis, cell survival, and tumor progression. Our copy therefore supports the mechanism and tumor-related roles, but not the claimed gene count; page numbers were not available. (LLM, conf=0.88)

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  • Many syndromes described above are accompanied by hypoxia, and this causes levels of HIF to increase.

    “Although I am mainly not concentrating on genetic regulatory aspects in this review, the HIF [2246,2247] does deserve some mention, since many of the syndromes described above are accompanied by hypoxia, and this causes levels of the HIF to increase.”

    From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [2246]

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Research works printed but not linked: 2

  1. [76]76. Rivard, A., Berthou-Soulie, L., Principe, N., Kearney, M., Curry, C., Branellec, D., Semenza, G.L., and Isner, J.M. 2000. Age- dependent defect in VEGF expression is associated with re- duced HIF-1 activity. J. Biol. Chem. (in press).
  2. [92]92. Sutter, C.H., Laughner, E., and Semenza, G.L. 2000. HIF-1␣ pro- tein expression is controlled by oxygen-regulated ubiquiti- nation that is disrupted by deletions and missense muta- tions. Proc. Natl. Acad. Sci. 97: 4748-4753.

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Authors
Semenza, G. L.
Affiliations
Johns Hopkins University (US)
Corresponding author
Semenza, Gregg L.
ORCID
Semenza, Gregg L.
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2000-08-15
Volume
14
Issue
16
Pages
1983-1991
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.14.16.1983
OpenAlex
W2112337731
Cited by
909
References
109
Citations by year
2026: 5 · 2025: 10 · 2024: 24 · 2023: 26 · 2022: 17 · 2021: 25 · 2020: 25 · 2019: 32 · 2018: 24 · 2017: 21 · 2016: 15 · 2015: 41 · 2014: 36 · 2013: 29 · 2012: 30
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • Children's Brain Tumor Foundation
  • 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 › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
oxygen homeostasis, hypoxia, vascular endothelial growth factor, angiogenesis, HIF-1, hypoxia response element, transcriptional activation, HIF-1α, ARNT, internal ribosome entry site, mRNA stabilization, heart disease
MeSH terms
Animals, Cardiovascular Diseases, Female, Humans, Neoplasms, Pregnancy, Pregnancy Complications, HIV-1

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