Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
Open accessAbstract
Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801 . Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.
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Redd1 is a new stress-induced protein and a negative regulator of mTOR through the TSC1/TSC2 complex.
“Redd1 is a new stress-induced protein and is known as a negative regulator of mTOR through TSC1/TSC2 complex [106–115].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [108]
The Discussion (page not supplied) describes Redd1 as stress-induced and reports that its suppression of mTOR signaling requires Tsc2. It presents signaling through the Tsc1/Tsc2 complex as the simplest model, however, and says a parallel pathway cannot be excluded; the claim states that mechanism more definitively than the paper does. (LLM, conf=0.85)
Experimental — accuracy not yet measuredUnder hypoxia, energy expenditure is decreased, leading to inhibition of high-energy-consuming events such as protein translation, leading to inhibition of mTOR and S6K.
“Under hypoxia, energy expenditure is decreased, leading to the inhibition of high–energy-consuming events such as protein translation, leading to the inhibition of mTOR and S6K (27).”
From Hypoxia decreases insulin signaling pathways in adipocytes. (2009) · cites this paper as [27]
TSC1/2 is responsive to hypoxia through the actions of REDD.
“TSC1/2 is also responsive to hypoxia through the actions of REDD (70).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [70]
Hypoxia-dependent regulation through REDD1 disrupts cytosolic 14-3-3-bound TSC2 and enables subsequent TSC2 localization to the lysosome where it can inhibit Rheb.
“Another example of this localization dependency includes hypoxia-dependent regulation through REDD1 (Brugarolas et al., 2004), which disrupts cytosolic 14-3-3-bound TSC2 and enables subsequent TSC2 localization to the lysosome where it can inhibit Rheb (DeYoung et al., 2008).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Brugarolas et al., 2004
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1 retracted
Dan, H. C., Sun, M., Yang, L., Feldman, R. I., Sui, X.-M., Ou, C. C., Nellist, M. D., Yeung, R. S. W., Halley, D. J. J., Nicosia, S. V., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205838200 · Cited by 370 · see citing works
RetractedThe phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621 · see citing works
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914 · see citing works
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083 · see citing works
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Inoki, K., Li, Y., Xu, T., & Guan, K.-L. (2003) · Genes & Development · doi:10.1101/gad.1110003 · Cited by 1,911 · see citing works
Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797 · see citing works
Self-citationHawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Mäkelä, T. P., Alessi, D. R., & Hardie, D. G. (2003) · Journal of Biology · doi:10.1186/1475-4924-2-28 · Cited by 1,666 · see citing works
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650 · see citing works
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555 · see citing works
Self-citationRegulation of translation initiation by FRAP/mTOR
Gingras, A.-C., Raught, B., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.887201 · Cited by 1,545 · see citing works
Fingar, D. C., & Blenis, J. (2004) · Oncogene · doi:10.1038/sj.onc.1207542 · Cited by 1,250 · see citing works
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C., & Blenis, J. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00506-2 · Cited by 1,211 · see citing works
Self-citationHudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., & Abraham, R. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7004-7014.2002 · Cited by 1,186 · see citing works
The AMP-activated protein kinase cascade – a unifying system for energy control
Carling, D. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.11.005 · Cited by 1,110 · see citing works
The LKB1 tumor suppressor negatively regulates mTOR signaling
Shaw, R. J., Bardeesy, N. M., Manning, B. D., Lopez, L. V., Kosmatka, M., DePinho, R. A., & Cantley, L. C. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.007 · Cited by 1,068 · see citing works
Self-citationInsulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2
Garami, A., Zwartkruis, F. J. T., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S. C., Hafen, E., Bos, J. L., & Thomas, G. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00220-x · Cited by 1,043 · see citing works
Self-citationAkt regulates growth by directly phosphorylating Tsc2
Potter, C. J., Pedraza, L. G., & Xu, T. (2002) · Nature Cell Biology · doi:10.1038/ncb840 · Cited by 959 · see citing works
Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins
Zhang, Y., Gao, X., Saucedo, L. J., Ru, B., Edgar, B. A., & Pan, D. (2003) · Nature Cell Biology · doi:10.1038/ncb999 · Cited by 924 · see citing works
HIF-1 and human disease: one highly involved factor
Semenza, G. L. (2000) · Genes & Development · doi:10.1101/gad.14.16.1983 · Cited by 909 · see citing works
Molecular basis of the VHL hereditary cancer syndrome
Kaelin, W. G. (2002) · Nature Reviews Cancer · doi:10.1038/nrc885 · Cited by 865 · see citing works
Self-citationRichard, D. E., Berra, E., Gothié, E., Roux, D., & Pouysségur, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32631 · Cited by 790 · see citing works
Pende, M., Um, S. H., Mieulet, V., Sticker, M., Goss, V. L., Mestan, J., Mueller, M., Fumagalli, S., Kozma, S. C., & Thomas, G. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.8.3112-3124.2004 · Cited by 743 · see citing works
Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling
Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R. S., Ru, B., & Pan, D. (2002) · Nature Cell Biology · doi:10.1038/ncb847 · Cited by 719 · see citing works
Ribosomal S6 Kinase Signaling and the Control of Translation
Dufner, A., & Thomas, G. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4683 · Cited by 676 · cited 4× · see citing works
“Thr 389 is the major rapamycin-sensitive site and can be phosphorylated by mTOR in vitro, suggesting that it is a direct mTOR target (Dufner and Thomas 1999).”
BackgroundInfluentialKwiatkowski, D. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.525 · Cited by 663 · see citing works
Rheb promotes cell growth as a component of the insulin/TOR signalling network
Saucedo, L. J., Gao, X., Chiarelli, D. A., Li, L., Pan, D., & Edgar, B. A. (2003) · Nature Cell Biology · doi:10.1038/ncb996 · Cited by 658 · see citing works
Carsillo, T., Astrinidis, A., & Henske, E. P. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.11.6085 · Cited by 648 · see citing works
Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products
van Slegtenhorst, M. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.6.1053 · Cited by 565 · see citing works
Corradetti, M. N., Inoki, K., Bardeesy, N. M., DePinho, R. A., & Guan, K. (2004) · Genes & Development · doi:10.1101/gad.1199104 · Cited by 556 · see citing works
Shoshani, T., Faerman, A., Mett, I., Zelin, E., Tenne, T., Gorodin, S., Moshel, Y., Elbaz, S., Budanov, A., Chajut, A., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.7.2283-2293.2002 · Cited by 546 · see citing works
The Drosophila Tuberous Sclerosis Complex Gene Homologs Restrict Cell Growth and Cell Proliferation
Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E., & Hariharan, I. K. (2001) · Cell · doi:10.1016/s0092-8674(01)00332-4 · Cited by 542 · see citing works
Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR
Zhang, H., Cicchetti, G., Onda, H., Koon, H. B., Asrican, K., Bajraszewski, N., Vázquez, F., Carpenter, C. L., & Kwiatkowski, D. J. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17222 · Cited by 538 · see citing works
Rheb is an essential regulator of S6K in controlling cell growth in Drosophila
Stocker, H., Radimerski, T., Schindelholz, B., Wittwer, F., Belawat, P., Daram, P., Breuer, S., Thomas, G., & Hafen, E. (2003) · Nature Cell Biology · doi:10.1038/ncb995 · Cited by 530 · see citing works
Self-citationTSC2 regulates VEGF through mTOR-dependent and -independent pathways
Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R., & Kaelin, W. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00187-9 · Cited by 528 · see citing works
Self-citationPotter, C. J., Huang, H., & Xu, T. (2001) · Cell · doi:10.1016/s0092-8674(01)00333-6 · Cited by 522 · see citing works
TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth.Preprint
Gao, X., & Pan, D. (2001) · Genes & Development · doi:10.1101/gad.901101 · Cited by 484 · see citing works
Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR
Zhang, H., Cicchetti, G., Onda, H., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200317222 · Cited by 482 · see citing works
Ellisen, L. W., Ramsayer, K. D., Johannessen, C. M., Yang, A., Beppu, H., Minda, K., Oliner, J. D., McKeon, F., & Haber, D. A. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00706-2 · Cited by 474 · see citing works
Self-citationArsham, A. M., Howell, J. J., & Simon, M. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212770200 · Cited by 463 · see citing works
Castro, A. F., Rebhun, J. F., Clark, G. J., & Quilliam, L. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300226200 · Cited by 381 · see citing works
Kimura, N., Tokunaga, C., Dalal, S., Richardson, C., Yoshino, K., Hara, K., Kemp, B. E., Witters, L. A., Mimura, O., & Yonezawa, K. (2003) · Genes to Cells · doi:10.1046/j.1365-2443.2003.00615.x · Cited by 372 · see citing works
Self-citationProliferation, But Not Growth, Blocked by Conditional Deletion of 40 S Ribosomal Protein S6
Volarević, S., Stewart, M. J., Ledermann, B., Zilbermann, F., Terracciano, L., Montini, E., Grompe, M., Kozma, S. C., & Thomas, G. (2000) · Science · doi:10.1126/science.288.5473.2045 · Cited by 372 · see citing works
Molecular genetic advances in tuberous sclerosis
Cheadle, J. P., Reeve, M. P., Sampson, J. R., & Kwiatkowski, D. J. (2000) · Human Genetics · doi:10.1007/s004390000348 · Cited by 350 · see citing works
Growth suppression by Lkb1 is mediated by a G 1 cell cycle arrest
Tiainen, M., Ylikorkala, A., & Mäkelä, T. P. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.16.9248 · Cited by 302 · see citing works
Reiling, J. H., & Hafen, E. (2004) · Genes & Development · doi:10.1101/gad.322704 · Cited by 291 · see citing works
Self-citationJaeschke, A., Hartkamp, J., Saitoh, M., Roworth, W., Nobukuni, T., Hodges, A., Sampson, J. R., Thomas, G., & Lamb, R. F. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.jcb.200206108 · Cited by 207 · see citing works
Steinman, R. A., Hoffman‐Liebermann, B., Liebermann, D. A., & Fisher, P. B. (1995) · Science · doi:10.1126/science.7716532 · Cited by 186 · see citing works
Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes
Brugarolas, J., & Kaelin, W. G. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.020 · Cited by 162 · see citing works
Self-citationEl-Hashemite, N., Walker, V., Zhang, H., & Kwiatkowski, D. J. (2003) · PubMed · Cited by 158 · see citing works
Lymphatics at the crossroads of angiogenesis and lymphangiogenesis
Scavelli, C., Weber, E., Aglianò, M., Cirulli, T., Nico, B., Vacca, A., & Ribatti, D. (2004) · Journal of Anatomy · doi:10.1111/j.0021-8782.2004.00293.x · Cited by 112 · see citing works
An activating mutation in the γ1 subunit of the AMP‐activated protein kinase
Hamilton, S. R., Stapleton, D., O’Donnell, J. B., Kung, J. T., Dalal, S. R., Kemp, B. E., & Witters, L. A. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02602-3 · Cited by 107 · see citing works
Self-citationRennebeck, G., Kleymenova, E., Anderson, R., Yeung, R. S. W., Artzt, K., & Walker, C. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15629 · Cited by 107 · see citing works
Karbowniczek, M., Cash, T. P., Cheung, M., Robertson, G. P., Astrinidis, A., & Henske, E. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402591200 · Cited by 99 · see citing works
Liu, M. Y., Poellinger, L., & Walker, C. L. (2003) · PubMed · Cited by 73 · see citing works
Loss of tuberin, the tuberous‐sclerosis‐complex‐2 gene product is associated with angiogenesis
Nguyen‐Vu, P., Fackler, I., Rust, A., et al. (2001) · Journal of Cutaneous Pathology · doi:10.1034/j.1600-0560.2001.028009470.x · Cited by 38 · see citing works
REDD2 Gene Is Upregulated by Modified LDL or Hypoxia and Mediates Human Macrophage Cell Death
Cuaz‐Pérolin, C., Furman, C., Larigauderie, G., Legedz, L., Lasselin, C., Copin, C., Jaye, M., Searfoss, G. H., Yu, K. T., Duverger, N., et al. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000142366.69080.c3 · Cited by 27 · see citing works
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Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555 · see citing works
TOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787 · see citing works
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · see citing works
Targeting hypoxia in cancer therapy
Wilson, W. R., & Hay, M. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3064 · Cited by 3,172 · see citing works
mTOR at the nexus of nutrition, growth, ageing and disease
Liu, G. Y., & Sabatini, D. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0199-y · Cited by 2,737 · see citing works
MTOR: a pharmacologic target for autophagy regulation
Kim, Y. C., & Guan, K.-L. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73939 · Cited by 2,126 · see citing works
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943 · see citing works
Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway
Park, K. K., Liu, K., Hu, Y., Smith, P. D., Wang, C., Cai, B., Xu, B., Connolly, L., Kramvis, I., Sahin, M., et al. (2008) · Science · doi:10.1126/science.1161566 · Cited by 1,686 · see citing works
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · see citing works
Hypoxia signalling in cancer and approaches to enforce tumour regression
Pouysségur, J., Dayan, F., & Mazure, N. M. (2006) · Nature · doi:10.1038/nature04871 · Cited by 1,676 · see citing works
Normalization of the Vasculature for Treatment of Cancer and Other Diseases
Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K. (2011) · Physiological Reviews · doi:10.1152/physrev.00038.2010 · Cited by 1,605 · see citing works
Bellot, G., Garcia-Medina, R., Gounon, P., Chiche, J., Roux, D., Pouysségur, J., & Mazure, N. M. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00166-09 · Cited by 1,501 · see citing works
Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks
Alers, S., Löffler, A. S., Wesselborg, S., & Stork, B. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06159-11 · Cited by 1,483 · see citing works
Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond
Lee, P., Chandel, N. S., & Simon, M. C. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0227-y · Cited by 1,272 · see citing works
PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase
Sancak, Y., Thoreen, C. C., Peterson, T. R., Lindquist, R. A., Kang, S. A., Spooner, E., Carr, S. A., & Sabatini, D. M. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.03.003 · Cited by 1,236 · see citing works
The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Huang, J., & Manning, B. D. (2008) · Biochemical Journal · doi:10.1042/bj20080281 · Cited by 1,237 · see citing works
Self-citationRegulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks
Magnuson, B., Ekim, B., & Fingar, D. C. (2012) · Biochemical Journal · doi:10.1042/bj20110892 · Cited by 1,015 · see citing works
Hypoxia signalling through mTOR and the unfolded protein response in cancer
Wouters, B. G., & Koritzinsky, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2501 · Cited by 894 · see citing works
Regulation of Immune Responses by mTOR
Powell, J. D., Pollizzi, K. N., Heikamp, E. B., & Horton, M. R. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075024 · Cited by 836 · see citing works
The mTOR Signalling Pathway in Human Cancer
Pópulo, H., Lopes, J. M., & Soares, P. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13021886 · Cited by 830 · see citing works
Bhaskar, P. T., & Hay, N. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.03.020 · Cited by 798 · see citing works
Regulation of mTORC1 by amino acids
Bar-Peled, L., & Sabatini, D. M. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.03.003 · Cited by 773 · see citing works
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Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717 · 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
Self-citationChen, C., Liu, Y., Liu, R., Ikenoue, T., Guan, K.-L., Liu, Y., & Zheng, P. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20081297 · Cited by 682 · see citing works
Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1
Ben Sahra, I., Regazzetti, C., Robert, G., Laurent, K., Le Marchand-Brustel, Y., Auberger, P., Tanti, J.-F., Giorgetti-Peraldi, S., & Bost, F. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-1769 · 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
Tsun, Z.-Y., Bar-Peled, L., Chantranupong, L., Zoncu, R., Wang, T., Kim, C., Spooner, E., & Sabatini, D. M. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.09.016 · Cited by 565 · see citing works
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Morita, M., Gravel, S.-P., Hulea, L., Larsson, O., Pollak, M., St-Pierre, J., & Topisirovic, I. (2015) · Cell Cycle · doi:10.4161/15384101.2014.991572 · Cited by 552 · see citing works
Signalling to translation: How signal transduction pathways control the protein synthetic machinery
Proud, C. G. (2007) · Biochemical Journal · doi:10.1042/bj20070024 · Cited by 520 · see citing works
Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis
Wenes, M., Shang, M., Di Matteo, M., Goveia, J., Martín-Pérez, R., Serneels, J., Prenen, H., Ghesquière, B., Carmeliet, P., & Mazzone, M. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.008 · Cited by 496 · see citing works
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Chantranupong, L., Wolfson, R. L., Orozco, J. M., Saxton, R. A., Scaria, S. M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S. P., & Sabatini, D. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.014 · Cited by 466 · see citing works
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Efeyan, A., Zoncu, R., & Sabatini, D. M. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.05.007 · Cited by 436 · see citing works
“In response to low oxygen, the transcription factor hypoxia inducible factor 1α (HIF-1α) drives an adaptive cellular program that induces, among other targets, the expression of Redd1, an activator of TSC2 and, hence, an mTORC1 inhibitor [15].”
BackgroundHashimoto, T., Horikawa, D. D., Saito, Y., Kuwahara, H., Kozuka-Hata, H., Shin-I, T., Minakuchi, Y., Ohishi, K., Motoyama, A., Aizu, T., et al. (2016) · Nature Communications · doi:10.1038/ncomms12808 · Cited by 394 · see citing works
<scp>mTOR</scp> , metabolism, and the regulation of T‐cell differentiation and function
Waickman, A. T., & Powell, J. D. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01152.x · Cited by 420 · see citing works
Wander, S. A., Hennessy, B. T., & Slingerland, J. M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44145 · Cited by 427 · see citing works
Hypoxia. 2. Hypoxia regulates cellular metabolism
Wheaton, W. W., & Chandel, N. S. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00485.2010 · Cited by 426 · see citing works
New frontiers in translational control of the cancer genome
Truitt, M. L., & Ruggero, D. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.27 · Cited by 378 · see citing works
Fyfe, J. J., Bishop, D. J., & Stepto, N. K. (2014) · Sports Medicine · doi:10.1007/s40279-014-0162-1 · Cited by 347 · see citing works
Emerling, B. M., Weinberg, F., Snyder, C., Burgess, Z., Mutlu, G. M., Viollet, B., Budinger, G. R. S., & Chandel, N. S. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.02.019 · Cited by 330 · see citing works
Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease
Fraisl, P., Aragonés, J., & Carmeliet, P. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2761 · Cited by 326 · see citing works
Coordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways
Levine, A. J., Feng, Z., Mak, T. W., You, H., & Jin, S. (2006) · Genes & Development · doi:10.1101/gad.1363206 · Cited by 321 · see citing works
An oxygen-regulated switch in the protein synthesis machinery
Uniacke, J., Holterman, C. E., Lachance, G., Franovic, A., Jacob, M. D., Fabian, M. R., Payette, J., Holcik, M., Pause, A., & Lee, S. (2012) · Nature · doi:10.1038/nature11055 · Cited by 319 · see citing works
Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis
Gao, J., Wei, B., de Assuncao, T. M., Liu, Z., Hu, X., Ibrahim, S., Cooper, S. A., Cao, S., Shah, V. H., & Kostallari, E. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.04.044 · Cited by 288 · see citing works
Hypoxia decreases insulin signaling pathways in adipocytes.
Regazzetti, C., Peraldi, P., Grémeaux, T., Najem-Lendom, R., Ben-Sahra, I., Cormont, M., Bost, F., Le Marchand-Brustel, Y., Tanti, J.-F., & Giorgetti-Peraldi, S. (2009) · Diabetes · doi:10.2337/db08-0457 · Cited by 281 · see citing works
The Role of p53 in Metabolic Regulation
Puzio-Kuter, A. M. (2011) · Genes & Cancer · doi:10.1177/1947601911409738 · Cited by 273 · see citing works
ERK1/2 Phosphorylate Raptor to Promote Ras-dependent Activation of mTOR Complex 1 (mTORC1)
Carriere, A., Romeo, Y., Acosta-Jaquez, H. A., Moreau, J., Bonneil, E., Thibault, P., Fingar, D. C., & Roux, P. P. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159046 · Cited by 268 · see citing works
mTORC1 Signaling under Hypoxic Conditions Is Controlled by ATM-Dependent Phosphorylation of HIF-1α
Cam, H., Easton, J. B., High, A., & Houghton, P. J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.10.030 · Cited by 266 · see citing works
Placental Responses to Changes in the Maternal Environment Determine Fetal Growth
Dimasuay, K. G., Boeuf, P., Powell, T. L., & Jansson, T. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00012 · Cited by 258 · see citing works
Corradetti, M. N., Inoki, K., & Guan, K.-L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c400557200 · Cited by 237 · see citing works
Malagelada, C., Jin, Z. H., & Greene, L. A. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3928-08.2008 · Cited by 228 · see citing works
Allen, E., Miéville, P., Warren, C. M., Saghafinia, S., Li, L., Peng, M.-W., & Hanahan, D. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.029 · Cited by 221 · see citing works
Differential Roles of GSK-3β During Myocardial Ischemia and Ischemia/Reperfusion
Zhai, P., Sciarretta, S., Galeotti, J., Volpe, M., & Sadoshima, J. (2011) · Circulation Research · doi:10.1161/circresaha.111.249532 · Cited by 218 · see citing works
Kim, S. G., Hoffman, G. R., Poulogiannis, G., Buel, G. R., Jang, Y. J., Lee, K. W., Kim, B.-Y., Erikson, R. L., Cantley, L. C., Choo, A. Y., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.10.003 · Cited by 215 · see citing works
Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
Liang, N., Zhang, C., Dill, P., Panasyuk, G., Pion, D., Koka, V., Gallazzini, M., Olson, E. N., Lam, H., Henske, E. P., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20140341 · Cited by 205 · see citing works
Hypoxic Reactive Oxygen Species Regulate the Integrated Stress Response and Cell Survival
Liu, L., Wise, D. R., Diehl, J. A., & Simon, M. C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805056200 · Cited by 206 · see citing works
Zimmer, M., Ebert, B. L., Neil, C., Brenner, K., Papaioannou, I., Melas, A., Tolliday, N., Lamb, J., Pantopoulos, K., Golub, T., et al. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.12.004 · Cited by 191 · see citing works
Hypoxia and Selective Autophagy in Cancer Development and Therapy
Daskalaki, I., Gkikas, I., & Tavernarakis, N. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00104 · Cited by 188 · see citing works
Common pitfalls in preclinical cancer target validation
Kaelin, W. G. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.32 · Cited by 175 · see citing works
Self-citationCrosstalk between Hypoxia and ER Stress Response: a Key Regulator of Macrophage Polarization
Díaz-Bulnes, P., Saiz, M. L., López-Larrea, C., & Rodríguez, R. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02951 · Cited by 175 · see citing works
van Vliet, T., Varela-Eirin, M., Wang, B., Borghesan, M., Brandenburg, S. M., Franzin, R., Evangelou, K., Seelen, M., Gorgoulis, V., & Demaria, M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.018 · Cited by 172 · see citing works
Xie, Z., Dong, Y., Zhang, M., Cui, M.-Z., Cohen, R. A., Riek, U., Neumann, D., Schlattner, U., & Zou, M.-H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511178200 · Cited by 172 · see citing works
Hypoxia suppresses conversion from proliferative arrest to cellular senescence
Leontieva, O. V., Natarajan, V., Demidenko, Z. N., Burdelya, L. G., Gudkov, A. V., & Blagosklonny, M. V. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205690109 · Cited by 169 · see citing works
Hypoxia-inducible factors: key regulators of myeloid cells during inflammation
Lin, N., & Simon, M. C. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84426 · Cited by 170 · see citing works
Lysosomal recruitment of TSC2 is a universal response to cellular stress
Demetriades, C., Plescher, M., & Teleman, A. A. (2016) · Nature Communications · doi:10.1038/ncomms10662 · Cited by 160 · see citing works
REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling
Dennis, M. D., Coleman, C. S., Berg, A., Jefferson, L. S., & Kimball, S. R. (2014) · Science Signaling · doi:10.1126/scisignal.2005103 · Cited by 159 · see citing works
The immunobiology of mTOR in autoimmunity
Suto, T., & Karonitsch, T. (2020) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.102373 · Cited by 149 · see citing works
Bartolomé, A., García-Aguilar, A., Asahara, S.-I., Kido, Y., Guillén, C., Pajvani, U. B., & Benito, M. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00441-17 · Cited by 141 · see citing works
Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells
Weichhart, T., Haidinger, M., Katholnig, K., Kopecky, C., Poglitsch, M., Lassnig, C., Rosner, M., Zlabinger, G. J., Hengstschläger, M., Müller, M., et al. (2011) · Blood · doi:10.1182/blood-2010-09-310888 · Cited by 141 · see citing works
HIF2α cooperates with RAS to promote lung tumorigenesis in mice
Kim, W. Y., Perera, S., Zhou, B., Carretero, J., Yeh, J. J., Heathcote, S. A., Jackson, A. L., Nikolinakos, P., Ospina, B., Naumov, G., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38443 · Cited by 141 · see citing works
Self-citationActivation of AMPK under Hypoxia: Many Roads Leading to Rome
Dengler, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072428 · Cited by 133 · see citing works
HIF-independent role of prolyl hydroxylases in the cellular response to amino acids
Durán, R. V., MacKenzie, E. D., Boulahbel, H., Frezza, C., Heiserich, L., Tardito, S., Bussolati, O., Rocha, S., Hall, M. N., & Gottlieb, E. (2013) · Oncogene · doi:10.1038/onc.2012.465 · Cited by 139 · see citing works
Hypoxia Tolerance in Animals: Biology and Application
Gorr, T. A., Wichmann, D., Hu, J., Hermes‐Lima, M., Welker, A. F., Terwilliger, N., Wren, J. F., Viney, M., Morris, S., Nilsson, G. E., et al. (2010) · Physiological and Biochemical Zoology · doi:10.1086/648581 · Cited by 134 · see citing works
Growth Control Under Stress: mTOR Regulation through the REDD1-TSC Pathway
Ellisen, L. W. (2005) · Cell Cycle · doi:10.4161/cc.4.11.2139 · Cited by 131 · see citing works
Self-citation<scp>TOR</scp>‐mediated regulation of metabolism in aging
Antikainen, H., Driscoll, M., Haspel, G., & Dobrowolski, R. (2017) · Aging Cell · doi:10.1111/acel.12689 · Cited by 122 · see citing works
Diouf, B., Cheng, Q., Krynetskaia, N. F., Yang, W., Cheok, M., Pei, D., Fan, Y., Cheng, C., Krynetskiy, E. Y., Geng, H., et al. (2011) · Nature Medicine · doi:10.1038/nm.2430 · Cited by 129 · see citing works
The role of hypoxia-inducible factor-2 in digestive system cancers
Zhao, J., Du, F., Shen, G., Zheng, F., & Xu, B. (2015) · Cell Death & Disease · doi:10.1038/cddis.2014.565 · Cited by 122 · see citing works
Di Conza, G., Trusso Cafarello, S., Loroch, S., Mennerich, D., Deschoemaeker, S., Di Matteo, M., Ehling, M., Gevaert, K., Prenen, H., Zahedi, R. P., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.01.051 · Cited by 119 · see citing works
Molitoris, J. K., McColl, K. S., Swerdlow, S., Matsuyama, M., Lam, M., Finkel, T. H., Matsuyama, S., & Distelhorst, C. W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.245423 · Cited by 96 · see citing works
Janaszak-Jasiecka, A., Bartoszewska, S., Kochan, K., Piotrowski, A., Kalinowski, L., Kamysz, W., Ochocka, R. J., Bartoszewski, R., & Collawn, J. F. (2016) · Scientific Reports · doi:10.1038/srep22775 · Cited by 81 · see citing works
New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress
Chen, B. P. C., Li, M., & Asaithamby, A. (2012) · Cancer Letters · doi:10.1016/j.canlet.2011.12.004 · Cited by 84 · see citing works
The role of the TOR pathway in mediating the link between nutrition and longevity
Lushchak, O., Strilbytska, O., Piskovatska, V., Storey, K. B., Koliada, A., & Vaiserman, A. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.03.005 · Cited by 73 · see citing works
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity
Ortmann, B. M. (2024) · BMJ Oncology · doi:10.1136/bmjonc-2023-000154 · Cited by 67 · see citing works
Andrysik, Z., Bender, H., Galbraith, M. D., & Espinosa, J. M. (2021) · Nature Communications · doi:10.1038/s41467-021-21687-2 · Cited by 63 · see citing works
REDD2-mediated inhibition of mTOR promotes dendrite retraction induced by axonal injury
Morquette, B., Morquette, P., Agostinone, J., Feinstein, E., McKinney, R. A., Kolta, A., & Di Polo, A. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.149 · Cited by 60 · see citing works
Cellular oxygen sensing, signalling and how to survive translational arrest in hypoxia
Fähling, M. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2008.01894.x · Cited by 57 · see citing works
Zhang, J., Cao, J., Weng, Q., Wu, R., Yan, Y., Jing, H., Zhu, H., He, Q., & Yang, B. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013910 · Cited by 56 · see citing works
Surviving hypoxia by modulation of mRNA translation rate
Fähling, M. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00875.x · Cited by 54 · see citing works
The mTOR pathway negatively controls ATM by up-regulating miRNAs
Shen, C., & Houghton, P. J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220898110 · Cited by 50 · see citing works
PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease
Morel, M., Couturier, J., Lafay‐Chebassier, C., Paccalin, M., & Page, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00849.x · Cited by 47 · see citing works
The p-rpS6-zone delineates wounding responses and the healing process
Ring, N. A. R., Dworak, H., Bachmann, B., Schädl, B., Valdivieso, K., Rozmaric, T., Heimel, P., Fischer, I., Klinaki, E., Gutasi, A., et al. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.04.001 · Cited by 31 · see citing works
Damjanac, M., Page, G., Ragot, S., Laborie, G., Gil, R., Hugon, J., & Paccalin, M. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00688.x · Cited by 31 · see citing works
Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12 · see citing works
- Authors
- Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., & Kaelin, W. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Dartmouth College (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2004-11-15
- Volume
- 18
- Issue
- 23
- Pages
- 2893-2904
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC534650
- OpenAlex
- W2115820946
- Cited by
- 1,384
- References
- 56
- Citations by year
- 2026: 49 · 2025: 43 · 2024: 46 · 2023: 68 · 2022: 71 · 2021: 94 · 2020: 74 · 2019: 66 · 2018: 57 · 2017: 68 · 2016: 65 · 2015: 55 · 2014: 83 · 2013: 77 · 2012: 80
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- 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
- U.S. Department of Defense
- Howard Hughes Medical Institute
- Barr Foundation
- National Institutes of Health
- National Cancer Institute (R01CA122589)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-35712, R01DK035712)
- 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
- mTOR, hypoxia, REDD1, RTP801, TSC1/TSC2 complex, tumor suppressor, hypoxia-inducible factor, S6K phosphorylation, 4E-BP1, AMPK, LKB1, mRNA synthesis, tumor suppression, cell proliferation
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Hypoxia, Cell Division, Mice, Inbred C57BL, Phosphorylation, Protein Kinases, Repressor Proteins, Transcription Factors, Down-Regulation, 3T3 Cells, Ribosomal Protein S6 Kinases, Tumor Suppressor Proteins, RNA, Small Interfering, Mice, TOR Serine-Threonine Kinases
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