Cited by 57Cancer, Hypoxia, and MetabolismRNA and protein synthesis mechanismsPI3K/AKT/mTOR signaling in cancer

Cellular oxygen sensing, signalling and how to survive translational arrest in hypoxia

Fähling, M.·2009·Acta Physiologica

Abstract

Hypoxia is a consequence of inadequate oxygen availability. At the cellular level, lowered oxygen concentration activates signal cascades including numerous receptors, ion channels, second messengers, as well as several protein kinases and phosphatases. This, in turn, activates trans‐factors like transcription factors, RNA‐binding proteins and miRNAs, mediating an alteration in gene expression control. Each cell type has its unique constellation of oxygen sensors, couplers and effectors that determine the activation and predominance of several independent hypoxia‐sensitive pathways. Hence, altered gene expression patterns in hypoxia result from a complex regulatory network with multiple divergences and convergences. Although hundreds of genes are activated by transcriptional control in hypoxia, metabolic rate depression, as a consequence of reduced ATP level, causes inhibition of mRNA translation. In a multi‐phase response to hypoxia, global protein synthesis is suppressed, mainly by phosphorylation of eIF2‐alpha by PERK and inhibition of mTOR, causing suppression of 5′‐cap‐dependent mRNA translation. Growing evidence suggests that mRNAs undergo sorting at stress granules, which determines the fate of mRNA as to whether being translated, stored, or degraded. Data indicate that translation is suppressed only at ‘free’ polysomes, but is active at subsets of membrane‐bound ribosomes. The recruitment of specific mRNAs into subcellular compartments seems to be crucial for local mRNA translation in prolonged hypoxia. Furthermore, ribosomes themselves may play a significant role in targeting mRNAs for translation. This review summarizes the multiple facets of the cellular adaptation to hypoxia observed in mammals.

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Crossref · 10.1111/j.1748-1716.2008.01894.x

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283 of 283 references verified0 citation errors · 0 not checkable

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  • PERK upregulates ATF4, which along with ATF6 and IRE1 pathways selectively regulates gene expression to assist the cell to tolerate hypoxia.

    “It also upregulates the transcription factor ATF4, which along with the ATF6 and IRE1 pathways selectively regulates gene expression to assist the cell to tolerate hypoxia (180, 343, 585).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [180]

  • UPR adaptations include increased amino acid transporter activity and enzyme expression to boost glutathione, stimulation of hematopoiesis, and upregulation of VEGF.

    “These adaptations include increased amino acid transporter activity and enzyme expression to boost the concentration of glutathione, the principal intracellular antioxidant, stimulation of hematopoiesis, and upregulation of the angiogenic growth factor VEGF.”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [180]

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Authors
Fähling, M.
Affiliations
Charité – Universitätsmedizin Berlin (DE)
Corresponding author
Fähling, M.
Venue
Acta Physiologica
Publisher
Wiley
Published
2009-01-05
Volume
195
Issue
2
Pages
205-230
ISSN
  • 1748-1708 (ISSN-L)
  • 1748-1716
OpenAlex
W2065309438
Cited by
57
References
283
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 2 · 2014: 2 · 2013: 8 · 2012: 5
FWCI
0.36
Type
journal article
Language
en
Open access
closed
Locations
  • Acta Physiologica (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
hypoxia, cellular oxygen sensing, hypoxia signaling, translational arrest, eIF2α phosphorylation, PERK, mTOR inhibition, stress granules, mRNA translation, membrane-bound ribosomes, local translation, transcriptional regulation, gene expression regulation
MeSH terms
Adenosine Triphosphate, Animals, Calcium, Cells, Gene Expression Regulation, Humans, Mammals, Oxygen, Ribosomes, Protein Biosynthesis, Cell Hypoxia, Reactive Oxygen Species, Reactive Nitrogen Species

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