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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Background
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Background
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BackgroundSelf-citation
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“[63] A.”
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BackgroundMethodInfluential
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Background
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Background
Sestrin2 maintains OXPHOS integrity to modulate cardiac substrate metabolism during ischemia and reperfusion
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“Young C57BL/6J mice (3–6 months, young-WT), Aged-WT C57BL/6 J mice (24–26 months, aged-WT) were provided by National Institute on Aging (NIA), the Sesn2 knockout (Sesn2 KO) (3–6 months, C57BL/6 J background), and its littermate mice were bred in our laboratory [13,16, 17].”
Method
SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health
Ro, S., Fay, J., Cyuzuzo, C. I., Jang, Y., Lee, N., Song, H., & Harris, E. N. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.603421 · Cited by 34
“Sestrin2 improves insulin sensitivity, prevents excessive lipid accumulation and alleviates ER stress by inhibiting mTORC1 through AMPK activation (Budanov and Karin, 2008) and GATOR binding (Chantranupong et al., 2014; Parmigiani et al., 2014; Kim J.S. et al., 2015) (Figure 1A).”
BackgroundInfluential
p53 induces a survival transcriptional response after nucleolar stress
Liao, H., Gaur, A., Mauvais, C., & Denicourt, C. (2021) · Molecular Biology of the Cell · doi:10.1091/mbc.e21-05-0251 · Cited by 33
“…this, we used RNAi to knock down ATG7, an E1-like activating enzyme essential for autophagy, and SESTRIN 2, which was shown to promote autophagy by activating an AMPK-dependent inhibition of mTOR signaling (Tanida et al. , 1999; Komatsu et al. , 2001; Budanov and Karin, 2008; Maiuri et al. , 2009).”
Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics
Phan, T. T. T., Lin, Y., Chou, Y., Wu, C., & Lin, L. (2022) · Oncogenesis · doi:10.1038/s41389-022-00401-x · Cited by 34
“The tumor suppressor p53, encoded by the tumor protein p53 (TP53) gene, is a master regulator of multiple cell fate-determining genes and prevents the oncogenic activation of the mTOR signaling pathway [22-25].”
Background
Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy
Fu, W., Liu, Y., Sun, C., & Yin, H. (2018) · The FASEB Journal · doi:10.1096/fj.201800577r · Cited by 33
Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations
Pujals, A., Favre, L., Pioche‐Durieu, C., Robert, A., Meurice, G., Gentil, M. L., Chelouah, S., Martin‐Garcia, N., Cam, É. L., Guettier, C., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1115939 · Cited by 34
“The proteins encoded by these genes are involved in a cascade of events: AMPK is activated by direct interactions with SESN1 and SESN2 and phosphorylates TSC2 which, in turn, inhibits MTOR thus leading to autophagy activation.(5) Treatment of BL2 and BL2/B95 with nutlin-3 did not modify the mRNA level of BECN1 (data n…”
Background
Upregulation of sestrins protect atriums against oxidative damage and fibrosis in human and experimental atrial fibrillation
Dong, Z., Lin, C., Liu, Y., Jin, H., Wu, H., Li, Z., Sun, L., Zhang, L., Hu, X., Wei, Y., et al. (2017) · Scientific Reports · doi:10.1038/srep46307 · Cited by 32
Increased plasma sestrin2 concentrations in patients with chronic heart failure and predicted the occurrence of major adverse cardiac events: A 36-month follow-up cohort study
Wang, H., Li, N., Shao, X., Li, J., Guo, L., Yu, X., Sun, Y., Hao, J., Niu, H., Xiang, J., et al. (2019) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.04.084 · Cited by 32
Ionizing Radiation and Translation Control: A Link to Radiation Hormesis?
Kabilan, U., Graber, T. E., Alain, T., & Klokov, D. Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186650 · Cited by 35
AMPK in myocardial infarction and diabetes: the yin/yang effect
Moussa, A., & Li, J. (2012) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2012.06.001 · Cited by 31
Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation
Yeo, S. Y., Itahana, Y., Guo, A. K., Han, R., Iwamoto, K., Nguyen, T., Bao, Y., Kleiber, K., Wu, Y., Bay, B., et al. (2016) · eLife · doi:10.7554/elife.07101 · Cited by 32
“…supplements induces TP53-dependent autophagy TP53 is known to induce autophagy, the catabolic breakdown of cellular components by the lysosome (Budanov and Karin, 2008; Crighton et al., 2006; Feng et al., 2005; Kenzelmann Broz et al., 2013), and autophagy can have a tumor suppressive function…”
Background
Inhibition of ERN1 modifies the hypoxic regulation of the expression of TP53-related genes in U87 glioma cells
Minchenko, D. O., Danilovskyi, S. V., Kryvdiuk, I. V., Bakalets, T. V., Lypova, N., Karbovskyi, L. L., & Minchenko, О. H. (2014) · Endoplasmic Reticulum Stress in Diseases · doi:10.2478/ersc-2014-0001 · Cited by 31
“SESN1 (sestrin 1 or TP53 regulated PA26 nuclear protein) and ZMAT3 (Zinc finger, Matrin-type 3 or TP53 target zinc finger protein) are TP53 target genes which have a role in the TP53-dependent growth regulatory pathway [26,27].”
Background
Integrating DNA damage response and autophagy signalling axis in ultraviolet-B induced skin photo-damage: a positive association in protecting cells against genotoxic stress
Umar, S. A., & Tasduq, S. A. (2020) · RSC Advances · doi:10.1039/d0ra05819j · Cited by 33
Sestrin2 suppression aggravates oxidative stress and apoptosis in endothelial cells subjected to pharmacologically induced endoplasmic reticulum stress
Fatima, M. T., Hasan, M. H., Abdelsalam, S. S., Sivaraman, S. K., Gamal, H. E., Zahid, M., Elrayess, M. A., Korashy, H. M., Zeidan, A., Parray, A., et al. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174247 · Cited by 33
USP8 inhibitor–induced DNA damage activates cell cycle arrest, apoptosis, and autophagy in esophageal squamous cell carcinoma
Sha, B., Sun, Y., Zhao, S., Li, M., Huang, W., Li, Z., Shi, J., Han, X., Li, P., Hu, T., et al. (2022) · Cell Biology and Toxicology · doi:10.1007/s10565-021-09686-x · Cited by 31
“Mechanistically, activation of p53 regulates autophagy through AMPKα activation and the inhibition of mTOR activity (Feng et al. 2005;Karuman et al. 2001;Budanov et al. 2008). p53 protein perhaps could form a complex with the LKB-1 kinase and regulate and activate AMPK (Karuman et al. 2001).”
Background
Tanshinone IIA Regulates Keap1/Nrf2 Signal Pathway by Activating Sestrin2 to Restrain Pulmonary Fibrosis
Li, H., Wu, M., Guo, C., Zhai, R., & Chen, J. (2022) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x22500914 · Cited by 34
Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes
Haley, V., Barnes, D., Sandovici, I., Constância, M., Graham, C. F., Pezzella, F., Bühnemann, C., Carter, E. J., & Hassan, A. B. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201101105 · Cited by 30
“Function of p53 may be mediated by Phlda3, a negative regulator of Akt (Brady et al, 2011), and via activation of PTEN (Stambolic et al, 2001), TSC2, AMP1 (Feng et al, 2007), sestrins 1 and 2 (Budanov & Karin, 2008) or REDD1 (Ellisen et al, 2002).”
Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming
Armstrong, L. C., Westlake, G. M., Snow, J. P., Cawthon, B., Armour, E. A., Bowman, A. B., & Ess, K. C. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx345 · Cited by 31
Insights into 4E-BP1 and p53 mediated regulation of accelerated cell senescence
Chao, S. K., Horwitz, S. B., & McDaid, H. M. (2011) · Oncotarget · doi:10.18632/oncotarget.221 · Cited by 30
“Since redox-impaired mutants were able to suppress mTORC1 as efficiently as wild type [55].”
Background
An ShRNA Based Genetic Screen Identified Sesn2 as a Potential Tumor Suppressor in Lung Cancer via Suppression of Akt-mTOR-p70S6K Signaling
Xu, H., Sun, H., Zhang, H., Liu, J., Fan, F., Li, Y., Ning, X., Sun, Y., Dai, S., Liu, B., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124033 · Cited by 30
“Furthermore, Sestrins mediate the DNA damage-sensing pathway composed of ataxia telangiectasia mutated (ATM) and p53, even though the underlying mechanism is unclear so far [16].”
BackgroundInfluential
Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status
de Oliveira, D. T., Sávio, A. L. V., Marcondes, J. P. D. C., Barros, T. M. B., Barbosa, L. C., Salvadori, D. M. F., & da Silva, G. N. (2016) · Journal of Biosciences · doi:10.1007/s12038-016-9654-5 · Cited by 30
“Indeed, simultaneous pharmacological modulation of p53 and AKT/mTOR pathway could provide enhanced anticancer efficacy through cell proliferation and growth inhibition (Budanov and Karin 2008; Levine and Oren 2009).”
Background
Pentamethylquercetin protects against cardiac remodeling via activation of Sestrin2
Du, J., Wu, J., Li, Z., Zhang, C., Shi, M., Zhao, J., Jin, M., & Liu, H. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.03.031 · Cited by 30
Ginseng metabolite Protopanaxadiol induces Sestrin2 expression and AMPK activation through GCN2 and PERK
Jin, H. R., Du, C. H., Wang, C., Yuan, C., & Du, W. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1548-7 · Cited by 30
Upregulation Sestrin2 protects against hydrogen peroxide‐induced oxidative damage bovine mammary epithelial cells via a Keap1‐Nrf2/ARE pathway
Chen, M., Xi, Y., Chen, K., Xiao, P., Li, S., Sun, X., & Han, Z. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29867 · Cited by 30
Flavonoids from Scutellaria barbata D. Don exert antitumor activity in colorectal cancer through inhibited autophagy and promoted apoptosis via ATF4/sestrin2 pathway
Liu, L., Liu, T., Tao, W., Liao, N., Yan, Q., Li, L., Tan, J., Shen, W., Cheng, H., & Sun, D. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154007 · Cited by 30
Gaining insight into the role of FoxO1 in the progression of disuse-induced skeletal muscle atrophy
Vilchinskaya, N. A., Altaeva, E. G., & Lomonosova, Y. N. (2022) · Advances in Biological Regulation · doi:10.1016/j.jbior.2022.100903 · Cited by 30
Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma
Chen, L., Pastorino, F., Berry, P., Bonner, J. J., Kirk, C., Wood, K. M., Thomas, H. D., Zhao, Y., Daga, A., Veal, G. J., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.32058 · Cited by 30
Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway
Liu, Y., Kim, H.-G., Dong, E., Dong, C., Huang, M., Liu, Y., Liangpunsakul, S., & Dong, X. C. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.07.011 · Cited by 30
Nck1 deficiency improves pancreatic β cell survival to diabetes-relevant stresses by modulating PERK activation and signaling
Yamani, L., Li, B., & Larose, L. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.09.016 · Cited by 28
Sestrin-3 modulation is essential for therapeutic efficacy of cucurbitacin B in lung cancer cells
Khan, N., Jajeh, F., Khan, M. I., Mukhtar, E., Shabana, S. M., & Mukhtar, H. (2016) · Carcinogenesis · doi:10.1093/carcin/bgw124 · Cited by 29
“Sestrins regulate the mTORC1 axis; their accumulation stimulates AMPK and inhibits TORC1, possibly by interacting with AMPK or causing increase in the abundance of AMPK subunits (24,25).”
Background
Biological Aspects of mTOR in Leukemia
Mirabilii, S., Ricciardi, M. R., Piedimonte, M., Gianfelici, V., Bianchi, M. P., & Tafuri, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082396 · Cited by 29
“Together, these observations highlighted that p53 inhibits mTOR by regulating a pathway that is used to detect nutrient/energy deprivation such as AMPK, and subsequently the TSC1/TSC2 complex [47].”
BackgroundInfluential
Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart
Quan, N., Li, X., Zhang, J., Han, Y., Sun, W., Ren, D., Tong, Q., & Li, J. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101637 · Cited by 29
“Previous studies showed that Sesn2 could inhibit mTORC1 through both AMPK-dependent and -independent pathways [27,34].”
BackgroundMethod
NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and Prospective Therapeutic Targets
Indini, A., Fiorilla, I., Ponzone, L., Calautti, E., & Audrito, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179985 · Cited by 31
p62/SQSTM1 is required for the protection against endoplasmic reticulum stress-induced apoptotic cell death
Park, J. S., Oh, S. Y., Lee, D. H., Lee, Y. S., Sung, S. H., Ji, H. W., Lee, M. J., Lee, Y., Rhee, S. G., & Bae, S. H. (2016) · Free Radical Research · doi:10.1080/10715762.2016.1253073 · Cited by 29
“Sestrin2 (Sesn2) is known as a stress responsive protein [24,35].”
BackgroundInfluential
Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy
Malik, B., Devine, H. E., Patani, R., Spada, A. R. L., Hanna, M. G., & Greensmith, L. (2019) · Scientific Reports · doi:10.1038/s41598-019-40118-3 · Cited by 29
Repositioning of niclosamide ethanolamine (NEN), an anthelmintic drug, for the treatment of lipotoxicity
Park, J. S., Lee, Y. S., Lee, D. H., & Bae, S. H. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.04.030 · Cited by 29
Longevity-Promoting Pathways and Transcription Factors Respond to and Control Extracellular Matrix Dynamics During Aging and Disease
Vidović, T., & Ewald, C. Y. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.935220 · Cited by 29
“Sestrins can activate AMPK, and the exact mechanism of this activation is unknown (Budanov and Karin, 2008).”
Background
Study on the Role and Mechanism of Exosomes Derived from Dental Pulp Stem Cells in Promoting Regeneration of Myelin Sheath in Rats with Sciatic Nerve Injury
Chai, Y., Liu, Y., Liu, Z., Wei, W., Dong, Y., Yang, C., & Chen, M. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-03960-9 · Cited by 28
“While P53 participates in the regulation of autophagy by regulating its downstream genes, such as mTOR pathway [26].”
Dynamics of the transcriptome response of cultured human embryonic stem cells to ionizing radiation exposure
Sokolov, M. V., Panyutin, I. V., Panyutin, I. G., & Neumann, R. D. (2011) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2011.02.008 · Cited by 29
“SESN1 provides a mechanistic link between genotoxic p53-mediated stress signaling and metabolic mTOR checkpoint [40], also being one of five genes constituting gene expression signature of IR exposure [37].”
Background
Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD
Heidler, J., Fysikopoulos, A., Wempe, F., Seimetz, M., Bangsow, T., Tomasovic, A., Veit, F., Scheibe, S., Pichl, A., Weisel, F. C., et al. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.013482 · Cited by 28
“However, independently of its antioxidant function, SESN2 inhibits mammalian target of rapamycin (mTOR) (Budanov and Karin, 2008), a prometabolic serine/threonine kinase that controls protein synthesis, cell growth, autophagy and cell death.”
Sestrin2 alleviates palmitate‐induced endoplasmic reticulum stress, apoptosis, and defective invasion of human trophoblast cells
Lee, S., Shin, J., Hong, Y.-J., Shin, S. M., Shin, H. W., Shin, J., Lee, S. K., & Park, H. (2020) · American Journal of Reproductive Immunology · doi:10.1111/aji.13222 · Cited by 28

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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