Hypoxic Reactive Oxygen Species Regulate the Integrated Stress Response and Cell Survival
Open accessAbstract
Under hypoxic conditions, cells suppress energy-intensive mRNA translation by modulating the mammalian target of rapamycin (mTOR) and pancreatic eIF2alpha kinase (PERK) pathways. Much is known about hypoxic inhibition of mTOR activity; however, the cellular processes activating PERK remain unclear. Since hypoxia is known to increase intracellular reactive oxygen species (ROS), we hypothesized that hypoxic ROS regulate mTOR and PERK to control mRNA translation and cell survival. Our data indicate that although exogenous ROS inhibit mTOR, eIF2alpha, and eEF2, mTOR and eEF2 were largely refractory to ROS generated under moderate hypoxia (0.5% O(2)). In direct contrast, the PERK/eIF2alpha/ATF4 integrated stress response (ISR) was activated by hypoxic ROS and contributed to global protein synthesis inhibition and adaptive ATF4-mediated gene expression. The ISR as well as exogenous growth factors were critical for cell viability during extended hypoxia, since ISR inhibition decreased the viability of cells deprived of O(2) and growth factors. Collectively, our data support an important role for ROS in hypoxic cell survival. Under conditions of moderate hypoxia, ROS induce the ISR, thereby promoting energy and redox homeostasis and enhancing cellular survival.
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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 [343]
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 [343]
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Oxyl radicals, redox-sensitive signalling cascades and antioxidants
Genestra, M. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.04.009 · Cited by 4,930 · see citing works
Kim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905 · see citing works
An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress
Harding, H. P., Zhang, Y., Zeng, H., Novoa, I., Lu, P. D., Calfon, M. A., Sadri, N., Yun, C., Popko, B., Paules, R. S., et al. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00105-9 · Cited by 3,336 · see citing works
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.012 · Cited by 2,267 · see citing works
Marciniak, S. J., Yun, C. Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H. P., & Ron, D. (2004) · Genes & Development · doi:10.1101/gad.1250704 · Cited by 2,004 · see citing works
Mitochondrial reactive oxygen species trigger hypoxia-induced transcription
Chandel, N. S., Maltepe, E., Goldwasser, E., Mathieu, C. E., Simon, M. C., & Schumacker, P. T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.20.11715 · Cited by 1,926 · see citing works
Self-citationEndoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword?
Malhotra, J. D., & Kaufman, R. J. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1782 · Cited by 1,555 · see citing works
Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing
Guzy, R. D., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K. D., Simon, M. C., Hammerling, U., & Schumacker, P. T. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.001 · Cited by 1,545 · see citing works
Self-citationFeedback Inhibition of the Unfolded Protein Response by GADD34-Mediated Dephosphorylation of eIF2α
Novoa, I., Zeng, H., Harding, H. P., & Ron, D. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.5.1011 · Cited by 1,392 · see citing works
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9361-9374.2003 · Cited by 1,386 · see citing works
Self-citationBrugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., & Kaelin, W. G. (2004) · Genes & Development · doi:10.1101/gad.1256804 · Cited by 1,384 · see citing works
Csordás, G., Renken, C. W., Várnai, P., Walter, L., Weaver, D., BUTTLE, K. F., Balla, T., Mannella, C. A., & Hajnóczky, G. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200604016 · Cited by 1,377 · see citing works
Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis
Scheuner, D. L., Song, B., McEwen, E. L., Liu, C., Laybutt, D. R., Gillespie, P. J., Saunders, T. L., Bonner‐Weir, S., & Kaufman, R. J. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00265-9 · Cited by 1,355 · see citing works
Cancer's Molecular Sweet Tooth and the Warburg Effect
Kim, J., & Dang, C. V. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1501 · Cited by 1,217 · see citing works
The role of oxygen availability in embryonic development and stem cell function
Simon, M. C., & Keith, B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2354 · Cited by 966 · see citing works
Self-citationHypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology
Semenza, G. L. (2001) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(01)02090-1 · Cited by 930 · see citing works
Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation
Brunelle, J. K., Bell, E. L., Quesada, N. M., Vercauteren, K., Tiranti, V., Zeviani, M., Scarpulla, R. C., & Chandel, N. S. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.002 · Cited by 763 · see citing works
Cullinan, S. B., & Diehl, J. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m314219200 · Cited by 739 · see citing works
Self-citationER stress‐regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
Bi, M., Naczki, C., Koritzinsky, M., Fels, D. R., Blais, J. D., Hu, N., Harding, H. P., Novoa, I., Varia, M. A., Raleigh, J. A., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600777 · Cited by 732 · see citing works
DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W. (2008) · Genes & Development · doi:10.1101/gad.1617608 · Cited by 710 · see citing works
Redox signaling: hydrogen peroxide as intracellular messenger
Rhee, S. G. (1999) · Experimental & Molecular Medicine · doi:10.1038/emm.1999.9 · Cited by 701 · see citing works
Koumenis, C., Naczki, C., Koritzinsky, M., Rastani, S., Diehl, J. A., Sonenberg, N., Koromilas, A. E., & Wouters, B. G. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7405-7416.2002 · Cited by 688 · see citing works
Self-citationIntracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes
Duranteau, J., Chandel, N. S., Kulisz, A., Shao, Z., & Schumacker, P. T. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.19.11619 · Cited by 679 · see citing works
HIF-1 as a target for drug development
Giaccia, A., Siim, B. G., & Johnson, R. S. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1199 · Cited by 631 · see citing works
The Endoplasmic Reticulum: Folding, Calcium Homeostasis, Signaling, and Redox Control
Görlach, A., Klappa, P., & Kietzmann, T. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1391 · Cited by 616 · see citing works
Hypoxia-induced energy stress regulates mRNA translation and cell growth
Liu, L., Cash, T. P., Jones, R. G., Keith, B., Thompson, C. B., & Simon, M. C. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.010 · Cited by 607 · see citing works
Self-citationMansfield, K. D., Guzy, R. D., Pan, Y., Young, R. M., Cash, T. P., Schumacker, P. T., & Simon, M. C. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.003 · Cited by 606 · see citing works
Self-citationAkt Maintains Cell Size and Survival by Increasing mTOR-dependent Nutrient Uptake
Edinger, A. L., & Thompson, C. B. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.01-12-0584 · Cited by 589 · see citing works
Growth factors can influence cell growth and survival through effects on glucose metabolism
Vander Heiden, M. G., Plas, D. R., Rathmell, J. C., Fox, C. J., Harris, M. H., & Thompson, C. B. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.17.5899-5912.2001 · Cited by 536 · see citing works
HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo
Gao, P., Zhang, H., Dinavahi, R., Li, F., Xiang, Y., Raman, V., Bhujwalla, Z. M., Felsher, D. W., Cheng, L., Pevsner, J., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.004 · Cited by 523 · see citing works
Arsham, A. M., Howell, J. J., & Simon, M. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212770200 · Cited by 463 · see citing works
Self-citationActivating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress
Blais, J. D., Filippenko, V., Bi, M., Harding, H. P., Ron, D., Koumenis, C., Wouters, B. G., & Bell, J. C. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.17.7469-7482.2004 · Cited by 447 · see citing works
Lum, J. J., Bui, T., Gruber, M., Gordan, J. D., DeBerardinis, R. J., Covello, K. L., Simon, M. C., & Thompson, C. B. (2007) · Genes & Development · doi:10.1101/gad.1529107 · Cited by 429 · see citing works
Self-citationXue, X., Piao, J., Nakajima, A., Komazawa‐Sakon, S., Kojima, Y., Mori, K., Yagita∥, H., Okumura, K., Harding, H. P., & Nakano, H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505818200 · Cited by 400 · see citing works
Perkins, G. A., Renken, C. W., Martone, M. E., Young, S. J., Ellisman, M. H., & Frey, T. (1997) · Journal of Structural Biology · doi:10.1006/jsbi.1997.3885 · Cited by 396 · see citing works
Cytoprotection by pre‐emptive conditional phosphorylation of translation initiation factor 2
Lu, P. D., Jousse, C., Marciniak, S. J., Zhang, Y., Novoa, I., Scheuner, D. L., Kaufman, R. J., Ron, D., & Harding, H. P. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600030 · Cited by 382 · see citing works
PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR
Bernardi, R., Guernah, I., Jin, D. K., Grisendi, S., Alimonti, A., Teruya‐Feldstein, J., Cordon‐Cardo, C., Simon, M. C., Rafii, S., & Pandolfi, P. P. (2006) · Nature · doi:10.1038/nature05029 · Cited by 379 · see citing works
Self-citationKoritzinsky, M., Magagnin, M. G., van den Beucken, T., Seigneuric, R., Savelkouls, K. G. M., Dostie, J., Pyronnet, S., Kaufman, R. J., Weppler, S. A., Voncken, J. W., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7600998 · Cited by 364 · see citing works
Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning
Cai, S.-L., Tee, A. R., Short, J. D., Bergeron, J. M., Kim, J., Shen, J., Guo, R., Johnson, C. L., Kiguchi, K., & Walker, C. L. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507119 · Cited by 359 · see citing works
Lu, L., Han, A., & Chen, J.-J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.23.7971-7980.2001 · Cited by 317 · see citing works
Hypoxia signalling controls metabolic demand
Brahimi-Horn, M. C., Chiche, J., & Pouysségur, J. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.02.003 · Cited by 298 · see citing works
Blais, J. D., Addison, C., Edge, R. E., Falls, T. J., Zhao, H., Wary, K. K., Koumenis, C., Harding, H. P., Ron, D., Holčı́k, M., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01145-06 · Cited by 295 · see citing works
Reactive Oxygen Species and Signal Transduction
Finkel, T. (2001) · IUBMB Life · doi:10.1080/15216540252774694 · Cited by 291 · see citing works
Reiling, J. H., & Hafen, E. (2004) · Genes & Development · doi:10.1101/gad.322704 · Cited by 291 · see citing works
Kim, Y.-J., Ahn, J., Liang, P., Ip, C. C. Y., Zhang, Y., & Park, Y.-M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2401 · Cited by 256 · see citing works
Hamanaka, R. B., Bennett, B. S., Cullinan, S. B., & Diehl, J. A. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-03-0268 · Cited by 250 · see citing works
Self-citationConnolly, E., Braunstein, S., Formenti, S., & Schneider, R. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.10.3955-3965.2006 · Cited by 233 · see citing works
“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways
Koumenis, C., & Wouters, B. G. (2006) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0150 · Cited by 228 · see citing works
Marciniak, S. J., García‐Bonilla, L., Hu, J., Harding, H. P., & Ron, D. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200508099 · Cited by 183 · see citing works
Patel, J. C., McLeod, L. E., Vries, R. G. J., Flynn, A., Wang, X., & Proud, C. G. (2002) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2002.02992.x · Cited by 171 · see citing works
Control of the hypoxic response through regulation of mRNA translation
Wouters, B. G., van den Beucken, T., Magagnin, M. G., Koritzinsky, M., Fels, D. R., & Koumenis, C. (2005) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2005.03.009 · Cited by 154 · see citing works
How oxygen makes its presence felt: Figure 1.Preprint
Kaelin, W. G. (2002) · Genes & Development · doi:10.1101/gad.1003602 · Cited by 149 · see citing works
The cellular oxygen tension regulates expression of the endoplasmic oxidoreductase ERO1‐Lα
Gess, B., Hofbauer, K., Wenger, R. H., Lohaus, C., Meyer, H. E., & Kurtz, A. (2003) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2003.03590.x · Cited by 132 · see citing works
Anoxia Is Necessary for Tumor Cell Toxicity Caused by a Low-Oxygen Environment
Papandreou, I., Krishna, C. H. R., Kaper, F., Cai, D., Giaccia, A. J., & Denko, N. C. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3395 · Cited by 127 · see citing works
Induction characteristics of oxygen regulated proteins
Heacock, C. S., & Sutherland, R. M. (1986) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(86)90155-0 · Cited by 119 · see citing works
Koritzinsky, M., Rouschop, K. M. A., van den Beucken, T., Magagnin, M. G., Savelkouls, K. G. M., Lambin, P., & Wouters, B. G. (2007) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2007.04.031 · Cited by 55 · see citing works
Magagnin, M. G., Koritzinsky, M., & Wouters, B. G. (2006) · Drug Resistance Updates · doi:10.1016/j.drup.2006.07.002 · Cited by 41 · see citing works
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Santos, C. X. C., Tanaka, L. Y., Wosniak, J., & Laurindo, F. R. M. (2009) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2625 · Cited by 572 · see citing works
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Kim, K. H., Jeong, Y. T., Kim, S. H., Jung, H. S., Park, K. S., Lee, H.-Y., & Lee, M.-S. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.09.026 · Cited by 112 · see citing works
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- Authors
- Liu, L., Wise, D. R., Diehl, J. A., & Simon, M. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Pennsylvania (US)
- Corresponding author
- Simon, M. Celeste
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 283
- Issue
- 45
- Pages
- 31153-31162
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2576535
- OpenAlex
- W2084109336
- Cited by
- 206
- References
- 57
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 4 · 2021: 14 · 2020: 13 · 2019: 14 · 2018: 11 · 2017: 16 · 2016: 8 · 2015: 14 · 2014: 14 · 2013: 17 · 2012: 7
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- National Institutes of Health (PO1 CA 104838)
- National Cancer Institute (P01CA104838)
- Abramson Family Cancer Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- hypoxia, reactive oxygen species, integrated stress response, PERK, eIF2α, ATF4, mTOR, elongation factor 2, mRNA translation inhibition, cell survival, growth factor deprivation, redox homeostasis, energy homeostasis
- MeSH terms
- Animals, Cell Survival, Gene Expression Regulation, Protein Kinases, Protein Biosynthesis, Cell Hypoxia, Eukaryotic Initiation Factor-2, Reactive Oxygen Species, eIF-2 Kinase, Peptide Elongation Factor 2, Mice, Activating Transcription Factor 4, TOR Serine-Threonine Kinases
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