Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1
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The tuberous sclerosis tumor suppressors TSC1 and TSC2 regulate the mTOR pathway to control translation and cell growth in response to nutrient and growth factor stimuli. We have recently identified the stress response REDD1 gene as a mediator of tuberous sclerosis complex (TSC)-dependent mTOR regulation by hypoxia. Here, we demonstrate that REDD1 inhibits mTOR function to control cell growth in response to energy stress. Endogenous REDD1 is induced following energy stress, and REDD1-/- cells are highly defective in dephosphorylation of the key mTOR substrates S6K and 4E-BP1 following either ATP depletion or direct activation of the AMP-activated protein kinase (AMPK). REDD1 likely acts on the TSC1/2 complex, as regulation of mTOR substrate phosphorylation by REDD1 requires TSC2 and is blocked by overexpression of the TSC1/2 downstream target Rheb but is not blocked by inhibition of AMPK. Tetracycline-inducible expression of REDD1 triggers rapid dephosphorylation of S6K and 4E-BP1 and significantly decreases cellular size. Conversely, inhibition of endogenous REDD1 by short interfering RNA increases cell size in a rapamycin-sensitive manner, and REDD1-/- cells are defective in cell growth regulation following ATP depletion. These results define REDD1 as a critical transducer of the cellular response to energy depletion through the TSC-mTOR pathway.
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Activation of AMPK can block mTOR and mTORC1 activity by phosphorylating and activating TSC2.
“activation of AMP activated protein kinase (AMPK), such as during decreased energy states, can block mTOR and mTORC1 activity by phosphorylating and activating TSC2 [29, 30].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [30]
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 [111]
Endogenous Redd1 is induced following energy stress and inhibition of endogenous Redd1 increases cell size in a rapamycin-sensitive manner.
“Data demonstrated that endogenous Redd1 is induced following energy stress and inhibition of endogenous Redd1 increases cell size in a rapamycin-sensitive manner [111].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [111]
Cites
The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621 · see citing works
Targeted mutation of the DNA methyltransferase gene results in embryonic lethality
Li, E., Bestor, T. H., & Jaenisch, R. (1992) · Cell · doi:10.1016/0092-8674(92)90611-f · Cited by 3,984 · 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
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 2× · see citing works
“We also examined phosphorylation of the S6K substrate ribosomal protein S6 at S235/S236, the major sites phosphorylated in a rapamycin-sensitive manner by activated S6K (11).”
BackgroundAdiponectin-mediated modulation of hypertrophic signals in the heart
Shibata, R., Ouchi, N., Ito, M., Kihara, S., Shiojima, I., Pimentel, D. R., Kumada, M., Sato, K., Schiekofer, S., Ohashi, K., et al. (2004) · Nature Medicine · doi:10.1038/nm1137 · Cited by 671 · 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
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Sorted by citations
Host microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569 · see citing works
Jung, C. H., Ro, S.-H., Cao, J., Otto, N. M., & Kim, D.-H. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.01.017 · Cited by 2,090 · 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
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
Regulation 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
Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889 · 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
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
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-citationNutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1
Um, S. H., D'Alessio, D., & Thomas, G. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.003 · Cited by 690 · see citing works
Chen, 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
Erny, D., Dokalis, N., Mezö, C., Castoldi, A., Mossad, O., Staszewski, O., Frosch, M., Villa, M., Fuchs, V., Mayer, A., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.10.010 · Cited by 478 · see citing works
mTOR: Role in cancer, metastasis and drug resistance
Murugan, A. K. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.003 · Cited by 483 · see citing works
mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer
Dann, S. G., Selvaraj, A., & Thomas, G. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.04.002 · Cited by 481 · 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
Howell, J. J., Hellberg, K., Turner, M., Talbott, G., Kolar, M. J., Ross, D. S., Hoxhaj, G., Saghatelian, A., Shaw, R. J., & Manning, B. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.12.009 · Cited by 408 · 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
Role of mTOR in physiology and pathology of the nervous system
Swiech, L., Perycz, M., Malik, A., & Jaworski, J. (2008) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2007.08.015 · Cited by 338 · 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
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
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
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
Carlson, E. S., Stead, J. D. H., Neal, C. R., Petryk, A., & Georgieff, M. K. (2007) · Hippocampus · doi:10.1002/hipo.20307 · Cited by 141 · 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-citationDi 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
Apró, W., Wang, L., Pontén, M., Blomstrand, E., & Sahlin, K. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00091.2013 · Cited by 109 · 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
TOR kinase complexes and cell migration
Liu, L., & Parent, C. A. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201102090 · Cited by 87 · 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
Chen Shang, Y., Zhong Chong, Z., Wang, S., & Maiese, K. (2013) · Current Neurovascular Research · doi:10.2174/156720213804806007 · Cited by 61 · see citing works
“In contrast, activation of AMP activated protein kinase (AMPK), such as during decreased energy states, can block mTOR and mTORC1 activity by phosphorylating and activating TSC2 [29, 30].”
BackgroundPKR, 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
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
- Authors
- Sofer, A., Lei, K., Johannessen, C. M., & Ellisen, L. W.
- Affiliations
- Harvard University (US)
- Corresponding author
- Ellisen, Leif W.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-07-01
- Volume
- 25
- Issue
- 14
- Pages
- 5834-5845
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1168803
- OpenAlex
- W2148197020
- Cited by
- 449
- References
- 7
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 10 · 2023: 22 · 2022: 19 · 2021: 28 · 2020: 22 · 2019: 21 · 2018: 17 · 2017: 21 · 2016: 20 · 2015: 17 · 2014: 30 · 2013: 21 · 2012: 27
- FWCI
- 7.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- National Institutes of Health
- National Cancer Institute (R01CA122589)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- REDD1, mTOR signaling, tuberous sclerosis complex, TSC1, TSC2, energy stress, ATP depletion, AMPK, Rheb, cell growth regulation, hypoxia, rapamycin sensitivity
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 2 Protein, AMP-Activated Protein Kinase Kinases, Animals, Energy Metabolism, Enzyme Activation, Humans, Neuropeptides, Phosphorylation, Protein Kinases, Repressor Proteins, Transcription Factors, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, RNA Interference, Cell Size, Mice, TOR Serine-Threonine Kinases
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