Cited by 1,326PI3K/AKT/mTOR signaling in cancerCancer-related Molecular PathwaysMetabolism, Diabetes, and Cancer

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p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling

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Budanov, Andrei V., Karin, Michael·2008·Cell

DOI 10.1016/j.cell.2008.06.028PMC PMC2758522

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Abstract

The tumor suppressor p53 is activated upon genotoxic and oxidative stress and in turn inhibits cell proliferation and growth through induction of specific target genes. Cell growth is positively regulated by mTOR, whose activity is inhibited by the TSC1:TSC2 complex. Although genotoxic stress has been suggested to inhibit mTOR via p53-mediated activation of mTOR inhibitors, the precise mechanism of this link was unknown. We now demonstrate that the products of two p53 target genes, Sestrin1 and Sestrin2, activate the AMP-responsive protein kinase (AMPK) and target it to phosphorylate TSC2 and stimulate its GAP activity, thereby inhibiting mTOR. Correspondingly, Sestrin2-deficient mice fail to inhibit mTOR signaling upon genotoxic challenge. Sestrin1 and Sestrin2 therefore provide an important link between genotoxic stress, p53 and the mTOR signaling pathway.

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Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
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
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
Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton
Sarbassov, D. D., Ali, S. M., Kim, D.-H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., & Sabatini, D. M. (2004) · Current Biology · doi:10.1016/j.cub.2004.06.054 · Cited by 2,665
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,365
p53 in health and disease
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,351

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Schlereth, K., Charles, J. P., Bretz, A. C., & Stiewe, T. (2010) · Cell Cycle · doi:10.4161/cc.9.20.13595 · Cited by 54
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Background
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Background
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Background
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Background
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Dash, S., Chava, S. P., Chandra, P. K., Balart, L. A., Wu, T., & Aydın, Y. (2016) · Hepatic Medicine Evidence and Research · doi:10.2147/hmer.s63700 · Cited by 46
Sestrin 2 suppresses cells proliferation through AMPK/mTORC1 pathway activation in colorectal cancer
Wei, J., Fang, M., Fu, Z.-X., Zhang, S., Guo, J., Wang, R., Lv, Z., & Xiong, Y.-F. (2017) · Oncotarget · doi:10.18632/oncotarget.17595 · Cited by 44
“Also, evidence showed that sestrin 2 could inhibit cell proliferation by arresting cells in the G1 phase of the cell cycle [39].”
Background
Sestrin2 overexpression alleviates hydrogen peroxide-induced apoptosis and oxidative stress in retinal ganglion cells by enhancing Nrf2 activation via Keap1 downregulation
Fan, Y.-Z., Yao, X., Xiong, L., & Wang, J. (2020) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2020.109086 · Cited by 44
Distinct Role of Sesn2 in Response to UVB‐Induced DNA Damage and UVA‐Induced Oxidative Stress in Melanocytes
Zhao, B., Shah, P., Qiang, L., He, T., Budanov, A., & He, Y. (2017) · Photochemistry and Photobiology · doi:10.1111/php.12624 · Cited by 44
“Lentiviral constructs expressing shNC (shLuc) and shSesn2 were generated as described previously (6,7).”
BackgroundMethodSelf-citation
Nutrient sensing signaling and metabolic responses in shrimp Litopenaeus vannamei under acute ammonia stress
Sui, Z., Wei, C., Wang, X., Zhou, H., Liu, C., Mai, K., & He, G. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.114672 · Cited by 42
Autophagy, a process within reperfusion injury: an update.
Thapalia, B. A., Zhou, Z., & Lin, X. (2014) · Europe PMC (PubMed Central) · Cited by 43
The chemopreventive activity of the butyric acid prodrug tributyrin in experimental rat hepatocarcinogenesis is associated with p53 acetylation and activation of the p53 apoptotic signaling pathway
de Conti, A., Tryndyak, V., Koturbash, I., Heidor, R., Kuroiwa‐Trzmielina, J., Ong, T. P., Beland, F. A., Moreno, F. S., & Pogribny, I. P. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt124 · Cited by 43
p53 Deletion or Hotspot Mutations Enhance mTORC1 Activity by Altering Lysosomal Dynamics of TSC2 and Rheb
Agarwal, S., Bell, C. M., Taylor, S. M., & Moran, R. G. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0159 · Cited by 43
“Complementation of the control of the mTORC1 pathway in p53 null cells by exogenous expression of TSC2 and Sestrin2 The lower levels of TSC2 colocalizing with the membraneboundmTORC1 complexes in p53null cells led us toquestion the cellular levels of TSC2 and of Sestrin2, a protein involved in TSC2 function (15).”
Background
Sestrin‑2 regulates podocyte mitochondrial dysfunction�and apoptosis under high‑glucose conditions via AMPK
Lin, Q., Ma, Y., Chen, Z., Hu, J., Chen, C., Fan, Y., Liang, W., & Ding, G. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4508 · Cited by 43
Kinase mTOR: Regulation and role in maintenance of cellular homeostasis, tumor development, and aging
Parkhitko, A. A., Favorova, O. O., Khabibullin, D., Anisimov, V. N., & Henske, E. P. (2014) · Biochemistry (Moscow) · doi:10.1134/s0006297914020023 · Cited by 44
Senescence regulation by mTOR
Dulic, V. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_2 · Cited by 42
Role of Autophagy in Capsaicin-Induced Apoptosis in U251 Glioma Cells
Liu, Y.-P., Dong, F., Chai, X., Zhu, S., Zhang, B., & Gao, D. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0254-y · Cited by 42
Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia
Tabe, Y., Tafuri, A., Sekihara, K., Yang, H., & Konopleva, M. Y. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1333600 · Cited by 44
“A newly demonstrated key factor of the mTOR feedback loop is FOXO1, which activates AMPK in a TSC2-dependent manner, thereby decreasing mTORC1 and AKT activation via suppression of the S6K feedback loop.”
BackgroundInfluential
SESN2 negatively regulates cell proliferation and casein synthesis by inhibition the amino acid-mediated mTORC1 pathway in cow mammary epithelial cells
Luo, C., Zhao, S., Zhang, M., Gao, Y., Wang, J., Hanigan, M. D., & Zheng, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-22208-w · Cited by 43
The interaction of Hemin and Sestrin2 modulates oxidative stress and colon tumor growth
Kim, H., Yin, K., Falcon, D. M., & Xue, X. (2019) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2019.04.025 · Cited by 44
“Previously, we and others have shown that loss of SESN2 promotes colon tumor growth through increased endoplasmic reticulum stress and p53mediated control over mTORC1 signaling (Ro et al., 2016; Budanov and Karin, 2008; Peng et al., 2014).”
Background
Autophagy: A Friend or Foe in Allergic Asthma?
Theofani, E., & Xanthou, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126314 · Cited by 44
“Under glucose starvation, AMPK activation promotes TFEB nuclear translocation, through the phosphorylation of ACSS2 (acetyl-CoA synthetase shortchain family member 2) [90] (Figure 1).”
BackgroundInfluential
p53-mediated AKT and mTOR inhibition requires RFX7 and DDIT4 and depends on nutrient abundance
Coronel, L., Häckes, D., Schwab, K., Riege, K., Hoffmann, S., & Fischer, M. (2021) · Oncogene · doi:10.1038/s41388-021-02147-z · Cited by 40
“Although Compound C is not AMPK-specific but inhibits numerous kinases [33], a knockdown of AMPKα1 in H1299 cells corroborated the hypothesis that AMPK might indeed contribute to p53-mediated mTORC1 inhibition [6].”
BackgroundInfluential
p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs
Yamashita, G., Takano, N., Kazama, H., Tsukahara, K., & Miyazawa, K. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01293-x · Cited by 45
“The sestrin, activated by DNA damage, directly binds to AMPK and promotes AMPK autophosphorylation [33, 34].”
Background
Upregulation of Sestrin2 Expression Protects Against Macrophage Apoptosis Induced by Oxidized Low-Density Lipoprotein
Hu, H., Shi, Z., Lin, X., Chen, S., Wang, Q.-Y., & Tang, S. (2015) · DNA and Cell Biology · doi:10.1089/dna.2014.2627 · Cited by 41
“Additionally, Sestrin-induced activation of AMPK and inhibition of TORC1 may be involved in reducing ROS production through increasing mitochondrial respiration efficiency (Bonawitz et al., 2007; Budanov and Karin, 2008; Zid et al., 2009).”
Background
Tumor suppression by p53 without apoptosis and senescence: conundrum or rapalog-like gerosuppression?
Blagosklonny, M. V. (2012) · Aging · doi:10.18632/aging.100475 · Cited by 41
“p53 can inhibit the PI3K/mTOR pathway [4-6, 14-17, 50].”
Background
Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer
Kosaka, T., Hongo, H., Miyazaki, Y. J., Nishimoto, K., Miyajima, A., & Oya, M. (2017) · Oncotarget · doi:10.18632/oncotarget.21147 · Cited by 41
“SESNs are stress responsive genes and are activates p53-dependent or independent manner [33, 34].”
Background
Sestrins are differentially expressed with age in the skeletal muscle of men: A cross-sectional analysis
Zeng, N., D’Souza, R. F., Mitchell, C. J., & Cameron‐Smith, D. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.05.006 · Cited by 42
“Sestrins can suppress mTORC1 by phosphorylating AMPKα (Budanov and Karin, 2008) and have been proposed to regulate autophagy, likely via AMPK and mTORC1 (Lee et al.”
Therapeutic potential of stromal cells of non-renal or renal origin in experimental chronic kidney disease
Rota, C., Morigi, M., Cerullo, D., Introna, M., Colpani, O., Corna, D., Capelli, C., Rabelink, T. J., Leuning, D. G., Rottoli, D., et al. (2018) · Stem Cell Research & Therapy · doi:10.1186/s13287-018-0960-8 · Cited by 41
Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration
Melnik, B. C. (2021) · Biomolecules · doi:10.3390/biom11030404 · Cited by 47
Azithromycin enhances the cytotoxicity of DNA‐damaging drugs via lysosomal membrane permeabilization in lung cancer cells
Toriyama, K., Takano, N., Kokuba, H., Kazama, H., Moriya, S., Hiramoto, M., Abe, S., & Miyazawa, K. (2021) · Cancer Science · doi:10.1111/cas.14992 · Cited by 42
The role of autophagy in anticancer therapy: promises and uncertainties
Tschan, M. P., & Simon, H. (2010) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2010.02266.x · Cited by 42
Autophagy: an adaptable modifier of tumourigenesis
Wilkinson, S., & Ryan, K. M. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.12.004 · Cited by 42
Inactivation of AMPK leads to attenuation of antigen presentation and immune evasion in lung adenocarcinoma
Gao, Y., Päivinen, P., Tripathi, S., Domènech-Moreno, E., Wong, I. P. L., Vaahtomeri, K., Nagaraj, A. S., Talwelkar, S. S., Foretz, M., Verschuren, E. W., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2049 · Cited by 40
Near-infrared light remotely up-regulate autophagy with spatiotemporal precision via upconversion optogenetic nanosystem
Pan, H., Wang, H., Yu, J., Huang, X. L., Hao, Y., Zhang, C., Ji, W., Yang, M., Gong, X., Wu, X., et al. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.01.042 · Cited by 40
Tandem mass tag labeling to characterize muscle-specific proteome changes in beef during early postmortem period
Zhai, C., Djimsa, B. A., Prenni, J. E., Woerner, D. R., Belk, K. E., & Nair, M. N. (2020) · Journal of Proteomics · doi:10.1016/j.jprot.2020.103794 · Cited by 42
Sestrin2 modulates cardiac inflammatory response through maintaining redox homeostasis during ischemia and reperfusion
Ren, D., Quan, N., Fedorova, J., Zhang, J., He, Z., & Li, J. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101556 · Cited by 41
“Sesn2 knockout (Sesn2-KO) (3–4 months, C57BL/6J) were bred and supplied by our lab as the previous reports described [15,20,21].”
Method
Profiling of circular RNAs in age-related cataract reveals circZNF292 as an antioxidant by sponging miR-23b-3p
Liang, S., Dou, S., Li, W., & Huang, Y. (2020) · Aging · doi:10.18632/aging.103683 · Cited by 40
“P53 target genes (Sestrin1 and Sestrin2) have been reported to provide an important link among stress, p53, and the mTOR signaling pathway [44].”
cep-1/p53-dependent dysplastic pathology of the aging C. elegans gonad
McGee, M. D., Day, N. U., Graham, J. B., & Melov, S. (2012) · Aging · doi:10.18632/aging.100448 · Cited by 40
“However, p53 has also been shown to be a regulator of growth via the IGF-1/mTOR pathway [23], and is an important part of the response to genotoxic stress [24,25].”
Background
Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m6A modification and diverse cell death mechanisms
Wang, X., Yang, J., Yang, W., Sheng, H., Jia, B., Peng, C., Xu, S., Hong, X., Jiang, C., Yang, Y., et al. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.10.026 · Cited by 46
“Moreover, genotoxic stress increases the expression of AMPK activators sestrins 1 and 2 in a p53-dependent manner, with sestrin 2 playing a critical role in autophagy induction in p53-proﬁcient cells under various stimuli [70].”
Targeting the liver kinase B1/AMP-activated protein kinase pathway as a therapeutic strategy for hematological malignancies
Martelli, A. M., Chiarini, F., Evangelisti, C., Ognibene, A., Bressanin, D., Billi, A. M., Manzoli, L., Cappellini, A., & McCubrey, J. A. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.694869 · Cited by 40
“Similar findings have been reported for AICAR-treated Jurkat T-ALL cells [126].”
BackgroundResult
RETRACTED ARTICLE: DDB2, an Essential Mediator of Premature Senescence
Roy, N., Stoyanova, T. I., Dominguez‐Brauer, C., Park, H. J., Bagchi, S., & Raychaudhuri, P. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01480-09 · Cited by 39
“The ROS scavenger MnSOD, glutathione peroxidase, catalase, and sestrin genes are activated by the FoxO family of transcription factors (FoxOs) (2, 3).”
Background
Retracted
Metformin: An Inhibitor of mTORC1 Signaling
Melnik, B. C., & Schmitz, G. (2014) · Cited by 39
P53 suppresses ribonucleotide reductase via inhibiting mTORC1
He, Z., Hu, X., Liu, W., Dorrance, A. M., Garzon, R., Houghton, P. J., & Shen, C. (2017) · Oncotarget · doi:10.18632/oncotarget.17440 · Cited by 41
“It has been well demonstrated that p53 suppresses mTORC1 signaling, leading to the proposal that one of the mechanisms by which p53 suppresses tumorigenesis is to downregulate mTORC1 [29, 37], but the underlying molecular mechanisms remain to be determined.”
Background
Sesn2 gene ablation enhances susceptibility to gentamicin-induced hair cell death via modulation of AMPK/mTOR signaling
Ebnöther, E., Ramseier, A., Cortada, M., Bodmer, D., & Levano, S. (2017) · Cell Death Discovery · doi:10.1038/cddiscovery.2017.24 · Cited by 41
The role of physical exercise on Sestrin1 and 2 accumulations in the skeletal muscle of mice
Crisol, B., Lenhare, L., Gaspar, R. S., Gaspar, R. C., Muñoz, V. R., da Silva, A. S. R., Cintra, D. E., de Moura, L. P., Pauli, J. R., & Ropelle, E. R. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.12.023 · Cited by 38
Sensors for the mTORC1 pathway regulated by amino acids
Li, X.-Z., & Yan, X. (2019) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b1900181 · Cited by 41

Authors: Budanov, A. V., & Karin, M.
Affiliations: University of California San Diego (US)
Corresponding author: Karin, Michael
ORCID: Budanov, Andrei V.
Karin, Michael
Venue: Cell
Publisher: Elsevier BV
Published: 2008-08
Volume: 134
Issue: 3
Pages: 451-460
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2008.06.028
PMC: PMC2758522
OpenAlex: W1972618720
Cited by: 1,326
References: 50
Citations by year: 2026: 31 · 2025: 56 · 2024: 60 · 2023: 56 · 2022: 86 · 2021: 94 · 2020: 110 · 2019: 85 · 2018: 81 · 2017: 85 · 2016: 87 · 2015: 78 · 2014: 85 · 2013: 71 · 2012: 89
FWCI: 23.26
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1847 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders: National Institute of Environmental Health Sciences (P42ES010337, 5R01 ES0637, R37ES004151, R01ES006376)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: p53, Sestrin2, mTOR signaling, TSC2, TSC1/TSC2 complex, AMPK, genotoxic stress, oxidative stress, p53 target genes, cell growth regulation, tumor suppression
MeSH terms: Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Sestrins, Animals, Cell Line, DNA Damage, Humans, Mice, Inbred C57BL, Multienzyme Complexes, Nuclear Proteins, Peroxidases, Proteins, Signal Transduction, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases

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p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling

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