Hypoxia-induced energy stress regulates mRNA translation and cell growth

Liu, Liping; Cash, Timothy P.; Jones, Russell G.; Keith, Brian; Thompson, Craig B.; Simon, M. Celeste

doi:10.1016/j.molcel.2006.01.010

Cited by 607PI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

Hypoxia-induced energy stress regulates mRNA translation and cell growth

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Liu, Liping, Cash, Timothy P., Jones, Russell G., Keith, Brian, Thompson, Craig B., Simon, M. Celeste·2006·Molecular Cell

DOI 10.1016/j.molcel.2006.01.010PMC PMC3153113

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Abstract

Oxygen (O2) deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O2 in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including eIF2alpha, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70S6K, and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK) activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G1 arrest. Together, eIF2alpha, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O2 conditions.

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AMPK phosphorylation of the tuberous sclerosis complex during hypoxia leads to inhibition of mTOR activity and conservation of cellular energy by inhibiting protein translation.
“This leads to inhibition of mTOR activity and further conservation of cellular energy by inhibiting the energetically-costly process of protein translation 24.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [24]
During hypoxia, AMPK phosphorylates and activates the tuberous sclerosis complex.
“In addition to regulating the Na/K-ATPase, AMPK phosphorylates and activates the tuberous sclerosis complex during hypoxia.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [24]

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Authors: Liu, L., Cash, T. P., Jones, R. G., Keith, B., Thompson, C. B., & Simon, M. C.
Affiliations: Howard Hughes Medical Institute (US)
University of Pennsylvania (US)
Corresponding author: Simon, M. Celeste
ORCID: Liu, Liping
Jones, Russell G.
Keith, Brian
Thompson, Craig B.
Simon, M. Celeste
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2006-02
Volume: 21
Issue: 4
Pages: 521-531
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2006.01.010
PMC: PMC3153113
OpenAlex: W2128677683
Cited by: 607
References: 40
Citations by year: 2026: 14 · 2025: 13 · 2024: 14 · 2023: 23 · 2022: 23 · 2021: 29 · 2020: 28 · 2019: 23 · 2018: 19 · 2017: 24 · 2016: 29 · 2015: 37 · 2014: 23 · 2013: 45 · 2012: 30
FWCI: 20.14
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2723 d)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Cancer Institute (P01CA104838)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: hypoxia, oxygen deprivation, energy stress, mRNA translation, eIF2α, elongation factor 2, mTOR signaling, 4E-BP1, p70S6K, ribosomal protein S6, AMPK, TSC2, Rheb, G1 cell cycle arrest, cell growth, bioenergetics
MeSH terms: Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Hypoxia, Carrier Proteins, Cell Line, Energy Metabolism, Enzyme Activation, Gene Expression Regulation, Humans, Multienzyme Complexes, Neuropeptides, Oxygen, Phosphoproteins, Protein Kinases, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Eukaryotic Initiation Factor-2, Protein Serine-Threonine Kinases, Cell Cycle Proteins, eIF-2 Kinase, Monomeric GTP-Binding Proteins, Peptide Elongation Factor 2, Tumor Suppressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, Adaptor Proteins, Signal Transducing, Hypoxia-Inducible Factor 1, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases

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Hypoxia-induced energy stress regulates mRNA translation and cell growth

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