PreprintCited by 710PI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and MetabolismTuberous Sclerosis Complex Research

The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.

Hypoxia regulates TSC1/2–mTOR signaling and tumor suppression through REDD1-mediated 14–3–3 shuttling

Open access

DeYoung, Maurice Phillip, Horak, Peter, Sofer, Avi, Sgroi, Dennis, Ellisen, Leif W.·2008·Genes & Development

DOI 10.1101/gad.1617608PMC PMC2192757

Open this paper in CoChat — free account Open PDF

Abstract

Hypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Drosophila and in mammalian cells. The molecular mechanism and physiologic significance of this effect of hypoxia remain unknown. Here, we demonstrate that hypoxia and REDD1 suppress mammalian TORC1 (mTORC1) activity by releasing TSC2 from its growth factor-induced association with inhibitory 14–3–3 proteins. Endogenous REDD1 is required for both dissociation of endogenous TSC2/14–3–3 and inhibition of mTORC1 in response to hypoxia. REDD1 mutants that fail to bind 14–3–3 are defective in eliciting TSC2/14–3–3 dissociation and mTORC1 inhibition, while TSC2 mutants that do not bind 14-3-3 are inactive in hypoxia signaling to mTORC1. In vitro, loss of REDD1 signaling promotes proliferation and anchorage-independent growth under hypoxia through mTORC1 dysregulation. In vivo, REDD1 loss elicits tumorigenesis in a mouse model, and down-regulation of REDD1 is observed in a subset of human cancers. Together, these findings define a molecular mechanism of signal integration by TSC1/2 that provides insight into the ability of REDD1 to function in a hypoxia-dependent tumor suppressor pathway.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1101/gad.1617608

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
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
Defining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833
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
The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress
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
The Tuberous Sclerosis Complex
Crino, P. B., Nathanson, K. L., & Henske, E. P. (2006) · New England Journal of Medicine · doi:10.1056/nejmra055323 · Cited by 1,793
Growing roles for the mTOR pathway
Sarbassov, D. D., Ali, S. M., & Sabatini, D. M. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.09.009 · Cited by 1,590
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway
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
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
Brugarolas, 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
Self-citation
Gene expression profiling identifies clinically relevant subtypes of prostate cancer
Lapointe, J., Li, C., Higgins, J., van de Rijn, M., Bair, E., Montgomery, K. D., Ferrari, M. K., Egevad, L., Rayford, W., Bergerheim, U. S. R., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0304146101 · Cited by 1,282

Flagged first, then by citations

Show all 41 references

Sorted by citations

Items 501–600 of 710

RTP801 Amplifies Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4–Dependent Oxidative Stress Induced by Cigarette Smoke
Hernández-Saavedra, D., Sanders, L., Perez, M. J., Kośmider, B., Smith, L. P., Mitchell, J. D., Yoshida, T., & Tuder, R. M. (2016) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2016-0144oc · Cited by 12
The involvement of regulated in development and DNA damage response 1 (REDD1) in the pathogenesis of intervertebral disc degeneration
Yin, H., Zhang, Y., Wang, K., Song, Y., Tu, J., Kang, L., Zhao, K., Wu, X., Luo, R., & Cao, Y. (2018) · Experimental Cell Research · doi:10.1016/j.yexcr.2018.10.001 · Cited by 12
Dietary caloric restriction protects experimental autoimmune uveitis by regulating Teff/Treg balance
Li, Z., Duan, R., Jiang, Q., Liu, J., Chen, J., Jiang, L., Wang, T., Li, H., Zhang, Y., Peng, X., et al. (2024) · iScience · doi:10.1016/j.isci.2024.111279 · Cited by 11
G-Protein Coupled Receptor Signaling and Mammalian Target of Rapamycin Complex 1 Regulation
Melick, C. H., Lama-Sherpa, T. D., Curukovic, A., & Jewell, J. L. (2021) · Molecular Pharmacology · doi:10.1124/molpharm.121.000302 · Cited by 11
Impact of Pyrrolidine Dithiocarbamate and Interleukin-6 on Mammalian Target of Rapamycin Complex 1 Regulation and Global Protein Translation
Song, S., Abdelmohsen, K., Zhang, Y., Becker, K. G., Gorospe, M., & Bernier, M. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.185678 · Cited by 11
Energy-Sensing Pathways in Ischemia: The Counterbalance Between AMPK and mTORC
Céspedes-Rubio, Á. E., Villa, M., Benito‐Cuesta, I., Pérez-Álvarez, M. J., Ordóñez‐Gutiérrez, L., & Wandosell, F. G. (2019) · Current Pharmaceutical Design · doi:10.2174/1381612825666191210152156 · Cited by 11
Western Diet-Mediated mTORC1-Signaling in Acne, Psoriasis, Atopic Dermatitis, and Related Diseases of Civilization: Therapeutic Role of Plant-Derived Natural mTORC1 Inhibitors
Melnik, B. C. (2012) · Humana Press eBooks · doi:10.1007/978-1-62703-167-7_37 · Cited by 11
REDD1 Is a Promising Therapeutic Target to Combat the Development of Diabetes Complications: A Report on Research Supported by Pathway to Stop Diabetes
Sunilkumar, S., & Dennis, M. D. (2024) · Diabetes · doi:10.2337/dbi24-0013 · Cited by 10
Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke
Beard, D. J., Brown, L. S., Morris, G. P., Couch, Y., Adriaanse, B. A., Karali, C. S., Schneider, A. M., Howells, D. W., Redzic, Z. B., Sutherland, B. A., et al. (2024) · Translational Stroke Research · doi:10.1007/s12975-024-01298-x · Cited by 10
Metabolic Regulation of T Cell Immunity
Vignali, P., Barbi, J. J., & Pan, F. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-94-024-1170-6_2 · Cited by 10
Whole Transcriptome Sequencing Reveals Cancer-Related, Prognostically Significant Transcripts and Tumor-Infiltrating Immunocytes in Mantle Cell Lymphoma
Sönmez, E. E., Hatipoğlu, T., Kurşun, D., Hu, X., Akman, B., Yuan, H., Danyeli, A. E., Alacacıoğlu, İ., Özkal, Ş., Olgun, A., et al. (2022) · Cells · doi:10.3390/cells11213394 · Cited by 10
mTOR
Castellanos, M., Gubern, C., & Kádár, E. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802733-2.00012-8 · Cited by 10
High-intensity interval training in hypoxia does not affect muscle HIF responses to acute hypoxia in humans
Smet, S. D., D’Hulst, G., Poffé, C., Thienen, R. V., Berardi, E., & Hespel, P. (2018) · European Journal of Applied Physiology · doi:10.1007/s00421-018-3820-4 · Cited by 10
TRIP4 transcriptionally activates DDIT4 and subsequent mTOR signaling to promote glioma progression
Li, W., Hu, S. C., Tian, C., Wan, X., Yu, W., Guo, P., Zhao, F. H., Hua, C., Lu, X., Xue, G., et al. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.10.009 · Cited by 10
Quinolinic acid induces cell apoptosis in PC12 cells through HIF-1-dependent RTP801 activation
Huang, X., Yang, K., Zhang, Y., Wang, Q., & Li, Y. (2016) · Metabolic Brain Disease · doi:10.1007/s11011-015-9782-x · Cited by 10
The Banking Systems of Germany, UK and Spain from a Spatial Perspective: The Spanish CasePreprint
GGrtner, S., & Fernnndez, J. (2018) · SSRN Electronic Journal · doi:10.2139/ssrn.3160010 · Cited by 10
Nuclear overexpression of DNA damage-inducible transcript 4 (DDIT4) is associated with aggressive tumor behavior in patients with pancreatic tumors
Tajik, F., Fattahi, F., Rezagholizadeh, F., Bouzari, B., Babaheidarian, P., Wadji, M. B., & Madjd, Z. (2023) · Scientific Reports · doi:10.1038/s41598-023-46484-3 · Cited by 13
The shared mechanism of barrier dysfunction in ulcerative colitis and Alzheimer’s disease: DDIT4/IL1β neutrophil extracellular traps drive macrophages-mediated phagocytosis
Li, S., Huang, Q., Yang, Q., Huang, Q., Wang, D.-X., Yang, J., Huang, S., Zhang, S.-Y., Wang, J., Xie, L., et al. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114188 · Cited by 12
TXNIP inhibits the progression of osteosarcoma through DDIT4-mediated mTORC1 suppression.
Yuan, Y., Liu, Q., Wu, Z., Zhong, W., Lin, Z., & Luo, W. (2022) · PubMed Central · Cited by 9
Transcription Factor EB: A Promising Therapeutic Target for Ischemic Stroke
Shao, J., Lang, Y., Ding, M., Yin, X. L., & Cui, L. (2023) · Current Neuropharmacology · doi:10.2174/1570159x21666230724095558 · Cited by 9
Recent insights into the pathophysiology of mTOR pathway dysregulation
Altomare, D. A., & Gitto, S. B. (2015) · Research and Reports in Biology · doi:10.2147/rrb.s57088 · Cited by 9
siRNA Knockdown of REDD1 Facilitates Aspirin-Mediated Dephosphorylation of mTORC1 Target 4E-BP1 in MDA-MB-468 Human Breast Cancer Cell Line
Savukaitytė, A., Gudoitytė, G., Bartnykaitė, A., Ugenskienė, R., & Juozaitytė, E. (2021) · Cancer Management and Research · doi:10.2147/cmar.s264414 · Cited by 9
ROCK ‘n TOR: An Outlook on Keratinocyte Stem Cell Expansion in Regenerative Medicine via Protein Kinase Inhibition
Centonze, G., Centonze, S., Ponzone, L., & Calautti, E. (2022) · Cells · doi:10.3390/cells11071130 · Cited by 9
Stress Responses Affecting Homeostasis of the Alveolar Capillary Unit
Tuder, R. M., & Yoshida, T. (2011) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201103-029mw · Cited by 9
KrasG12D-LOH promotes malignant biological behavior and energy metabolism of pancreatic ductal adenocarcinoma cells through the mTOR signaling pathway
Shen, X., CHANG, L. G., Hu, M., Yan, D., Zhou, L., MA, Y., Ling, S., Fu, Y., ZHANG, S. Y., Kong, B., et al. (2018) · Neoplasma · doi:10.4149/neo_2018_170224n142 · Cited by 9
Cancer Metabolism under Limiting Oxygen ConditionsPreprint
Kim, L. C., Lesner, N. P., & Simon, M. C. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041542 · Cited by 11
Cell Type‐Specific mTORC1 Signaling and Translational Control in Synaptic Plasticity and Memory
Huang, Z., Mahmood, N., Wiebe, S. A., Khoutorsky, A., Lacaille, J., & Sonenberg, N. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70281 · Cited by 10
Hamartin-Hsp70 Interaction Is Necessary for Akt-Dependent Tuberin Phosphorylation during Heat Shock
Inoue, H., Ndong, M., Suzuki, T., Kazami, M., Uyama, T., Kobayashi, K., Tadokoro, T., & Yamamoto, Y. (2009) · Bioscience Biotechnology and Biochemistry · doi:10.1271/bbb.90489 · Cited by 8
Comparative Proteomic Approach in Rat Model of Absence Epilepsy
Gürol, G., Demiralp, D. Ö., Yılmaz, A. K., Akman, Ö., Ateş, N., & Karson, A. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0402-8 · Cited by 8
Novel Stem Cell Strategies with mTOR
Maiese, K. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802733-2.00020-7 · Cited by 8
Translational Control by Amino Acids and Energy
Thedieck, K., & Hall, M. N. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00274-6 · Cited by 8
Loss of the vitamin D receptor triggers senescence in chronic myeloid leukemia via DDIT4-mediated DNA damage
Xu, Y., Qi, W., Zheng, C., Li, Y., Lu, Z., Guan, J., Lu, C., & Zhao, B. (2023) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjad066 · Cited by 7
A review of the participation of DDIT4 in the tumor immune microenvironment through inhibiting PI3K-Akt/mTOR pathway
Jiao, Y., & Xiang, Y. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1595463 · Cited by 10
APEX2-Mediated Proximity Labeling Resolves the DDIT4-Interacting Proteome
Naki, M., Gourdomichali, O., Zonke, K., Kattan, F.-G., Makridakis, M., Kontostathi, G., Vlahou, A., & Doxakis, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095189 · Cited by 7
Research Translation and Personalized Medicine
Brugarolas, J. (2012) · Springer eBooks · doi:10.1007/978-1-4614-2400-0_8 · Cited by 7
2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice
Zhang, J., Zhang, L., Chen, D., Fu, Y., Zhang, F., Yang, L., Xia, C.-M., Jiang, H., Tang, C., Xie, Z., et al. (2015) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.149 · Cited by 7
The TSC1–TSC2 Complex
(2010) · The Enzymes · doi:10.1016/s1874-6047(10)28002-2 · Cited by 8
Recombinant Tumor Suppressor TSC1 Differentially Interacts with Escherichia coli DnaK and Human HSP70
Natarajan, N., Shaik, A., & Thiruvenkatam, V. (2020) · ACS Omega · doi:10.1021/acsomega.0c02480 · Cited by 7
Non‐canonical STAT3 function reduces REDD1 transcription
Köhler, N., Wundrack, N., Schulz, S., Bartonitz, F., Schaper, F., & Dittrich, A. (2022) · FEBS Journal · doi:10.1111/febs.16679 · Cited by 7
miR-222-3p is involved in neural tube closure by directly targeting Ddit4 in RA induced NTDs mouse model
Sun, Y., Zhang, J., Wang, Y., Wang, L., Song, M., Khan, A., Zhang, L., Niu, B., Zhao, H., Li, M., et al. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1982506 · Cited by 7
Transcriptional changes in dendritic cells underlying allergen specific induced tolerance in a mouse model
Núñez, R., Rodríguez, M. J., Palomares, F., Gómez, F., Jabato, F. M., Caballero, J., Seoane, P., Losada, J., Rojo, J., Torres, M. J., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-06186-8 · Cited by 7
Tumour Hypoxia and the Hypoxia-Inducible Transcription Factors: Key Players in Cancer Progression and Metastasis
Jögi, A. (2015) · Springer eBooks · doi:10.1007/978-3-7091-1824-5_4 · Cited by 7
The mTOR Pathway and Aging
Schreiber, K. H., O’Leary, M. N., & Kennedy, B. K. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-411596-5.00002-2 · Cited by 7
The regulation of bcr-abl in hypoxia is through the mTOR pathway
Clapper, E., Trapani, G. D., & Tonissen, K. F. (2020) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2020.1849679 · Cited by 7
REDD1 Expression in Placenta During Human Gestation
Hu, Y. Y., Liu, J. C., Xing, A., You, Y., & Wang, X. D. (2012) · Reproductive Sciences · doi:10.1177/1933719112440054 · Cited by 7
Growth-induced physiological hypoxia correlates with growth deceleration during normal developmentPreprint
Zhao, Y., Alexandre, C., Kelly, G. P., Perez‐Mockus, G., & Vincent, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.04.597345 · Cited by 7
The effects of 1,25(OH)2D3 treatment on metabolic reprogramming and maturation in bone marrow-derived dendritic cells from control and diabetic mice
Shin, U., You, H., Lee, G. Y., Son, Y., & Han, S. N. (2022) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2022.106197 · Cited by 6
Myeloid PTEN loss affects the therapeutic response by promoting stress granule assembly and impairing phagocytosis by macrophages in breast cancer
Li, Y., Xu, C., Qian, X., Wang, G., Han, C., Hua, H., Dong, M., Chen, J., Yu, H., Zhang, R., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02094-0 · Cited by 6
The Mechanism of Adaptation of Breast Cancer Cells to Hypoxia: Role of AMPK/mTOR Signaling Pathway
Sorokin, D. V., Scherbakov, A. M., Ia, Y., Semina, S. E., Gudkova, M. V., & Ma, K. (2016) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-016-3217-5 · Cited by 6
Succinylsulfathiazole modulates the mTOR signaling pathway in the liver of c57BL/6 mice via a folate independent mechanism
Beydoun, S., Fardous, A. M., Saruna, M. M., Beydoun, A. G., Sorge, J. A., Ma, H., Aoun, G., Unnikrishnan, A., Cabelof, D. C., & Heydari, A. R. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111387 · Cited by 6
High Prevalence of Non-Responders Based on Quadriceps Force after Pulmonary Rehabilitation in COPD
Desachy, M., Alexandre, F., Varray, A. L., Molinier, V., Four, E., Charbonnel, L., & Héraud, N. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12134353 · Cited by 6
Mammalian target of rapamycin inhibition protects glioma cells from temozolomide-induced cell death
Sauer, B., Lorenz, N. I., Divé, I., Klann, K., Luger, A., Urban, H., Schröder, J.-H., Steinbach, J. P., Münch, C., & Ronellenfitsch, M. W. (2024) · Cell Death Discovery · doi:10.1038/s41420-023-01779-2 · Cited by 6
Regulation of protein and mRNA expression of the mTORC1 repressor REDD1 in response to leucine and serum
Black, A. J., Gordon, B. S., Dennis, M. D., Jefferson, L. S., & Kimball, S. R. (2016) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2016.10.003 · Cited by 6
Potential of mTOR inhibitors as therapeutic agents in hematological malignancies
Sankhala, K. K., & Giles, F. J. (2009) · Expert Review of Hematology · doi:10.1586/ehm.09.31 · Cited by 6
Transcriptional and epigenetic regulation of autophagy: mechanisms, disease relevance and therapeutic opportunities
Seo, J., Park, S., Lee, D. C., Yoo, W., Yang, Y. R., Seo, H. W., Park, J. L., Joo, J., Park, K. C., & Byun, S. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02688-3 · Cited by 5
Myxozoans (Cnidaria) do not Retain Key Oxygen-Sensing and Homeostasis Toolkit Genes
Graham, A. M., & Barreto, F. S. (2023) · Genome Biology and Evolution · doi:10.1093/gbe/evad003 · Cited by 5
A new posttranslational regulation of REDD1/DDIT4 through cleavage by caspase 3 modifies its cellular function
Puissant, A., Fenouille, N., Robert, G., Jacquel, A., Bassil, C. F., Colosetti, P., Luciano, F., & Auberger, P. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.291 · Cited by 5
Therapeutic options for lymphangioleiomyomatosis (LAM): where we are and where we are going
Taveira‐DaSilva, A. M., Steagall, W. K., & Moss, J. (2009) · F1000 Medicine Reports · doi:10.3410/m1-93 · Cited by 5
Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells
Nandi, P., Jang, C. E., Biggar, K. K., Halari, C. D., Jansson, T., & Gupta, M. B. (2021) · Biomolecules · doi:10.3390/biom11091382 · Cited by 5
Hypoxia
Jensen, C. C., & Warfel, N. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00039-6 · Cited by 5
The promoter methylation drives down-regulation mode of HIC1 in gastric cancer, its molecular characteristics and downstream functional pathways
Zhao, T., Yang, T., Zhang, J., Hao, H., Wang, D., Afirifa, J., Cai, M., Cui, X., Bai, J., Fu, S., et al. (2022) · Gene · doi:10.1016/j.gene.2022.146380 · Cited by 5
l-Asparaginase regulates mTORC1 activity via a TSC2-dependent pathway in pancreatic beta cells
Seike, M., Asahara, S., Inoue, H., Kudo, M., Kanno, A., Yokoi, A., Suzuki, H., Kimura-Koyanagi, M., Kido, Y., & Ogawa, W. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.02.035 · Cited by 5
ATM: Promoter of Metabolic “Cost” Reduction and “Savings” Usage during Hypoxia through mTORC1 Regulation
Kim, S. G., Choo, A. Y., & Blenis, J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.11.013 · Cited by 5
Vhl Dependent Expression of REDD1 and PDK3 Proteins in Clear-Cell Renal Cell Carcinoma
Ilic, B. B., Antic, J. A., Bankovic, J. Z., Milicevic, I., Rodic, G., Ilic, D. S., Tulić, C., Todorovic, V. N., & Damjanovic, S. S. (2017) · Journal of Medical Biochemistry · doi:10.1515/jomb-2017-0030 · Cited by 5
DDIT4 Novel Mutations in Pancreatic Cancer
Ding, F., Hong, X., Fan, X., Huang, S., Lian, W., Chen, X., Liu, Q., Chen, Y., & Gao, F. (2021) · Gastroenterology Research and Practice · doi:10.1155/2021/6674404 · Cited by 5
Early Stress-Response Gene REDD1 Controls Oxazolone-Induced Allergic Contact Dermatitis
Mirzoeva, S., Yang, Y., Kłopot, A., Budunova, I. V., & Brown, M. A. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100279 · Cited by 5
mTOR as a Modulator of Metabolite Sensing Relevant to Angiogenesis
Soumya, S. J., Athira, A. P., Binu, S., & Sudhakaran, P. R. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802733-2.00014-1 · Cited by 5
Glutaminase I and glutamine transaminase–ω-amidase pathways in colorectal cancer: Metabolic reprogramming and emerging therapeutic strategies
Voor, S. F., Cooper, A. J. L., & Pinto, J. T. (2025) · Analytical Biochemistry · doi:10.1016/j.ab.2025.115989 · Cited by 4
microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting
Tomasini, S., Monteleone, E., Altieri, A., Margiotta, F., Dardmeh, F., Alipour, H., Holm, A., Kauppinen, S., & Panella, R. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26209900 · Cited by 4
Sirolimus for the treatment of Graves’ orbitopathy
Comi, S., Sabini, E., Cosentino, G., Santini, F., & Marinò, M. (2025) · Thyroid Research · doi:10.1186/s13044-025-00273-4 · Cited by 4
The Duration of Glucocorticoid Treatment Alters the Anabolic Response to High Force Muscle Contractions.
Dunlap, K. R., Steiner, J., Hickner, R., Chase, P., & Gordon, B. S. (2023) · Journal of applied physiology · doi:10.1152/japplphysiol.00113.2023 · Cited by 4
Deciphering the intricate role of mTOR signaling and autophagy in Parkinson's disease and therapeutic prospect
Narayanan, L., Thekkekkara, D., Kondaveeti, S. N., Babu, A., Sailen, B. A., Chidambaram, S. B., & Manjula, S. N. (2024) · Journal of Applied Pharmaceutical Science · doi:10.7324/japs.2023.156692 · Cited by 4
mTOR and Regulation of Translation
Tsukumo, Y., Laplante, M., Parsyan, A. E., Ruggero, D., & Fonseca, B. D. (2014) · Springer eBooks · doi:10.1007/978-94-017-9078-9_15 · Cited by 5
Validation of a commercially available anti-REDD1 antibody using RNA interference and REDD1-/- mouse embryonic fibroblasts
Grainger, D., Kutzler, L., Rannels, S. L., & Kimball, S. R. (2016) · F1000Research · doi:10.12688/f1000research.7691.1 · Cited by 4
HIF-1α regulates mTOR signaling pathway during salivary gland development
Kimura, T., Sakai, M., Gojo, N., Watanabe, M., Uzawa, N., & Sakai, T. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.09.078 · Cited by 4
DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice
Colas, C., Mouchiroud, M., Dow, M. A., Kolnohuz, A., Gélinas, Y., Caron, A., & Laplante, M. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101660 · Cited by 4
Mechanisms driving fasting-induced protection from genotoxic injury in the small intestine
Deans-Fielder, K., Wu, T., Nguyen, T., To, S., Huang, Y., Bark, S. J., Mills, J. C., & Shroyer, N. F. (2024) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00126.2023 · Cited by 4
Phosphorylated mTOR is associated to androgen receptor expression in early triple-negative breast cancer
Pistelli, M., Ballatore, Z., Santinelli, A., Biscotti, T., Piva, F., Occhipinti, G., Mora, A. D., Pagliacci, A., Battelli, N., Bastianelli, L., et al. (2016) · Oncology Reports · doi:10.3892/or.2016.4903 · Cited by 4
mTORC1 Signaling and Hypoxia
Brugarolas, J. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-271-1_4 · Cited by 4
Commentary: Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia–Reperfusion With Increased Blood–Brain Barrier Disruption
Beard, D. J., Hadley, G., Sutherland, B. A., & Buchan, A. M. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.761556 · Cited by 4
The Role of mTOR Signaling in Tumor-Induced Alterations to Neuronal Function in Diffusely Infiltrating Glioma
Haile, H., Leskinen, S., Adapa, A. R., Goldberg, A. R., Viswanathan, A., Milligan, C., Conboy, K., Schevon, C. A., Canoll, P., & Gill, B. J. A. (2025) · Biomedicines · doi:10.3390/biomedicines13112593 · Cited by 3
Hypoxia-mediated regulation of mRNA metabolism: from transcription to stability
Zhang, X., Zhang, P., Zhang, C., Yuan, Z., & Li, S. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02471-x · Cited by 3
REDD1/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2/DR5 in cancer cells
Mora-Molina, R., Yousfi, Y. E., Hagenlocher, C., Fernández-Farrán, F. J., Rehm, M., Palacios, C., Christophorou, M. A., & López‐Rivas, A. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08648-7 · Cited by 3
Development and validation of disulfidptosis-related genes signature for patients with glioma
Wang, J., Luo, J., Yang, S., Deng, Y., Chen, P., Tan, Y. C., & Liu, Y. (2024) · Discover Oncology · doi:10.1007/s12672-024-01664-z · Cited by 4
Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity
Heikkinen, A., Esser, V. F. C., Lee, S. H., Lundgren, S., Hakkarainen, A., Lundbom, J., Kuula, J., Groop, P., Heinonen, S., Villicaña, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59576-7 · Cited by 3
DDIT4 Downregulation by siRNA Approach Increases the Activity of Proteins Regulating Fatty Acid Metabolism upon Aspirin Treatment in Human Breast Cancer Cells
Savukaitytė, A., Bartnykaitė, A., Bekampytė, J., Ugenskienė, R., & Juozaitytė, E. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45060296 · Cited by 3
Isometric contraction induces transient increase of REDD1 expression in non‐contracted muscles partly through glucocorticoids
Murakami, T. (2023) · Physiological Reports · doi:10.14814/phy2.15745 · Cited by 3
Involvement of mTOR signaling in physiopathology and its potential therapeutic interventions
Martín-Bocanegra, I., Horne, T. L., Maqueda-Hernández, B., Navarro‐Villarán, E., & Muntané, J. (2023) · Redox Experimental Medicine · doi:10.1530/rem-23-0024 · Cited by 3
mTOR Signalling Pathway-protein Expression in Post-transplant Cutaneous Squamous-cell Carcinomas Before and After Conversion to mTOR-inhibitors
Κoletsa, T., Petrakis, G., Karayannopoulou, G., Euvrard, S., & Kanitakis, J. (2018) · Anticancer Research · doi:10.21873/anticanres.12597 · Cited by 3
Inhibiteurs de mTOR : de l’explication biologique à l’application thérapeutique en hématologie
Balsat, M., & Cornillon, J. (2011) · Bulletin du Cancer · doi:10.1684/bdc.2011.1413 · Cited by 3
TOR Signaling and Cell Death
Wang, T., & Edgar, B. A. (2010) · The Enzymes · doi:10.1016/s1874-6047(10)28011-3 · Cited by 3
Von Hippel–Lindau tumor suppressor (VHL) stimulates TOR signaling by interacting with phosphoinositide 3-kinase (PI3K)
Hwang, S.-H., Bang, S., Kim, W., & Chung, J. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011596 · Cited by 3
The Role of Leucine and Its Metabolite (KIC) in Insulin Signalling and Glucose Transport in L6 Myotubes
Moghei, M. (2015) · YorkSpace (York University) · Cited by 3
Severe inbreeding and gene loss in the historical and extant population of the critically endangered Devils Hole pupfishPreprint
Tian, D., Turner, B. J., & Martin, C. (2021) · bioRxiv · doi:10.1101/2021.08.13.456274 · Cited by 1
Nrf2-and p53-inducible REDD2/DDiT4L/Rtp801L confers pancreatic β-cell dysfunction, leading to glucose intolerance in high-fat diet-fed mice
Yamada, Y., Urakawa, N., Tamiya, H., Sakamoto, S., Takahashi, H., Harada, N., Kitakaze, T., Izawa, T., Matsumura, S., Yoshihara, E., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110271 · Cited by 3
The potential role of hydrogen sulfide-autophagy axis in diseases
Chu, T., Wang, Y.-W., Cao, L., Wang, X., Fan, Y.-Q., Chen, Y., Zhang, Y., Si, W.-R., Jiang, Q., & Wu, D. (2025) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-025-01128-0 · Cited by 2
HIF-1α-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development
Zhao, Y., Alexandre, C., Kelly, G., Vincent, J., & Perez‐Mockus, G. (2025) · Nature Communications · doi:10.1038/s41467-025-67089-6 · Cited by 2
MUC1 in cancer
Qian, K., Zhang, Y., Zhou, Q., 周建明, Wu, X., Zhu, J., Pan, Y. P., Wu, Z., Li, S., Lin, Y., et al. (2026) · Holistic Integrative Oncology · doi:10.1007/s44178-026-00257-w · Cited by 2
PGK1 mediates glycolysis and cell proliferation in endometriosis by regulating DDIT4 nuclear translocation
Zhang, X., Wang, Y., Tang, Y., Wei, R., Zhao, R., Yu, Z., & Lü, C. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2025.120009 · Cited by 3
[Effect of PI3K/AKT pathway on cisplatin resistance in non-small cell lung cancer].
Zhang, Y., Lu, H., & Xu, G. (2014) · Europe PMC (PubMed Central) · doi:10.3779/j.issn.1009-3419.2014.08.09 · Cited by 2

Authors: DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W.
Affiliations: Harvard University (US)
ORCID: DeYoung, Maurice Phillip
Horak, Peter
Sgroi, Dennis
Ellisen, Leif W.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2008-01-15
Volume: 22
Issue: 2
Pages: 239-251
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.1617608
PMC: PMC2192757
OpenAlex: W2130396048
Cited by: 710
References: 41
Citations by year: 2026: 24 · 2025: 26 · 2024: 17 · 2023: 32 · 2022: 37 · 2021: 43 · 2020: 34 · 2019: 38 · 2018: 41 · 2017: 42 · 2016: 44 · 2015: 42 · 2014: 48 · 2013: 45 · 2012: 47
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA122589)
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
Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
Keywords: hypoxia, TSC1/2, mTORC1, REDD1, 14-3-3 proteins, TORC1 inhibition, tumor suppression, anchorage-independent growth, carcinogenesis, cellular metabolism, signal integration
MeSH terms: Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Breast Neoplasms, Cells, Cultured, Humans, Mice, Nude, Models, Biological, Neoplasm Transplantation, Protein Kinases, Transcription Factors, Signal Transduction, Cell Hypoxia, Tumor Suppressor Proteins, Mice, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Hypoxia regulates TSC1/2–mTOR signaling and tumor suppression through REDD1-mediated 14–3–3 shuttling

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks