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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“In addition, mTOR inhibition and the induction of autophagy have been linked to p53 and Ataxia-telangiectasia mutated (ATM) signaling after DNA damage, with ATM activation also occurring by reactive oxygen species in the cytoplasm (57, 58).”
Background
Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53
Miyamoto, T., Lo, P. H. Y., Saichi, N., Ueda, K., Hirata, M., Tanikawa, C., & Matsuda, K. (2017) · Science Advances · doi:10.1126/sciadv.1603204 · Cited by 60
“We next examined Akt and the downstream mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway, whose phosphorylation statuses are variable in response to genotoxic stress (38).”
Background
Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-β1/Smad3 axis in diabetic kidney disease
Song, S., Shi, C., Bian, Y., Yang, Z., Mu, L., Wu, H., Duan, H., & Shi, Y. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05120-0 · Cited by 59
“Sestrin2 is recognized as a highly conserved gene that is sensitive to stress or DNA damage [27].”
p53/TAp63 and AKT Regulate Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling through Two Independent Parallel Pathways in the Presence of DNA Damage
Cam, M., Bid, H. K., Xiao, L., Zambetti, G. P., Houghton, P. J., & Çam, H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.530303 · Cited by 60
“It has been shown previously that, in response to genotoxic stress, the tumor suppressor protein p53 is activated and inhibits mTORC1 signaling by inducing the transcription of the SESTRIN1/2 genes (10).”
Background
Emerging Roles of Sestrins in Neurodegenerative Diseases: Counteracting Oxidative Stress and Beyond
Chen, S., Yang, J., Lin, T., & Yang, D. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8071001 · Cited by 56
“Sestrins, a family of stress-inducible proteins, are activated and upregulated upon exposure to hypoxia [5], oxidative stress [16], as well as genotoxic stress [6,17].”
Background
Causes and consequences of DNA damage-induced autophagy
Juretschke, T., & Beli, P. (2021) · Matrix Biology · doi:10.1016/j.matbio.2021.02.004 · Cited by 59
Recent advances in anti-inflammation via AMPK activation
Xu, Y., Bai, L., Yang, X., Huang, J.-L., Wang, J., Wu, X., & Shi, J. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33670 · Cited by 71
Tumor TP53 expression status, body mass index and prognosis in colorectal cancer
Morikawa, T., Kuchiba, A., Liao, X., Imamura, Y., Yamauchi, M., Qian, Z. R., Nishihara, R., Sato, K., Meyerhardt, J. A., Fuchs, C. S., et al. (2011) · International Journal of Cancer · doi:10.1002/ijc.26495 · Cited by 57
“TP53 can also activate PRKA (AMPK), and promote the PRKA pathway to inhibit MTOR signaling and reduce cell growth, thereby help cell balance its growth and proliferation.(10) Given the link between energy balance and the TP53 pathway, energy balance may be important in determining biological behavior in TP53-negative…”
Background
Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine
Lang, C. H., Frost, R. A., Bronson, S. K., Lynch, C. J., & Vary, T. C. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00676.2009 · Cited by 57
“Although selective cellular stresses have also been reported to inhibit both basal and insulin-induced activation of mTOR activity via p53-dependent upregulation of Sestrin2 (Sesn2) (6), no change in Sesn2 content was observed in muscle from mTOR / and WT mice or in response to LPS (data not shown).”
Background
Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma
Syed, D. N., Lall, R. K., Chamcheu, J. C., Haidar, O., & Mukhtar, H. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.06.034 · Cited by 57
“AMPK plays a critical role in tumorigenesis through regulation of cell proliferation and apoptosis by phosphorylating key substrates, such as p53 and p27Kip1 (14).”
Background
Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress
Jegal, K. H., Ko, H. L., Park, S. M., Byun, S. H., Kang, K. W., Cho, I. J., & Kim, S. C. (2016) · APOPTOSIS · doi:10.1007/s10495-016-1233-6 · Cited by 57
“transcriptionally regulated by the activations of Nrf2 [17], HIF, p53 [14], c-jun [18], and ATF4 [43].”
Sestrin 3 Protects Against Diet‐Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor β Signal Transduction
Huang, M., Kim, H.-G., Zhong, X., Dong, C., Zhang, B., Fang, Z., Zhang, Y., Lu, X., Saxena, R., Liu, Y., et al. (2019) · Hepatology · doi:10.1002/hep.30820 · Cited by 57
ATF4-Mediated Upregulation of REDD1 and Sestrin2 Suppresses mTORC1 Activity during Prolonged Leucine Deprivation
Xu, D., Dai, W., Kutzler, L., Lacko, H. A., Jefferson, L. S., Dennis, M. D., & Kimball, S. R. (2019) · Journal of Nutrition · doi:10.1093/jn/nxz309 · Cited by 57
“However, in contrast to REDD1, the Sestrins do not act through the Akt pathway to repress mTORC1, but instead bind to and activate AMPK (11).”
BackgroundInfluential
p53 induces skin aging by depleting Blimp1+ sebaceous gland cells
Kim, J., Nakasaki, M., Todorova, D., Lake, B. B., Yuan, C.-Y., Jamora, C., & Xu, Y. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.87 · Cited by 55
Autophagy and senescence, stress responses induced by the DNA-damaging mycotoxin alternariol
Solhaug, A., Torgersen, M. L., Holme, J. A., Lagadic‐Gossmann, D., & Eriksen, G. S. (2014) · Toxicology · doi:10.1016/j.tox.2014.10.009 · Cited by 57
“Downstream of Sestrin2 the AMPK is activated and mTOR is suppressed (Budanov and Karin 2008), thereby releasing the negative regulation on autophagy (Jung et al. 2010).”
Background
p53 as an intervention target for cancer and aging
Hasty, P., & Christy, B. A. (2013) · Pathobiology of Aging & Age-related Diseases · doi:10.3402/pba.v3i0.22702 · Cited by 57
“p53 regulates the transcription of a large number of genes with a myriad of anti-oncogenic functions that include cell cycle arrest (p21, GADD45, 14-3-3s, RPRM), apoptosis (Scotin, Killer, FAS, BBC3, PERP, 53BP1, BAX, LRDD, PMAIP1), suppression of aerobic glycolysis (GLUT1, TIGAR, hexokinase, phosphoglycerate mutase),…”
Background
PIASy-mediated Tip60 sumoylation regulates p53-induced autophagy
Naidu, S. R., Lakhter, A. J., & Androphy, E. J. (2012) · Cell Cycle · doi:10.4161/cc.21091 · Cited by 58
“p53 integrates signals that originate from various stress responses in a complex growth-promoting environment and promotes autophagy.(20,21) How posttranslational modifications of p53 discriminate its selectivity for each of these transcriptional targets and the respective biological programs to induce apoptosis or au…”
Background
Mitochondrial dysfunction in metabolism and ageing: shared mechanisms and outcomes?
López‐Lluch, G., Hernández‐Camacho, J. D., Fernández‐Ayala, D. J. M., & Navas, P. (2018) · Biogerontology · doi:10.1007/s10522-018-9768-2 · Cited by 60
Wip1 phosphatase: between p53 and MAPK kinases pathways
Goloudina, A. R., Kochetkova, E. Y., Pospelova, T. V., & Demidov, O. N. (2016) · Oncotarget · doi:10.18632/oncotarget.7325 · Cited by 58
“p53 binds to the promoters of genes, the protein products of which regulate autophagy, including upstream regula tors, such as the β1, β2 and γ-subunits of AMP-activated protein kinase (AMPK), several regulators of the AMPK and mTOR1 complexes, sestrin 1 and sestrin 2 proteins, connect genotoxic stress and mTOR signal…”
Background
A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling
Zhang, J., Wei, J., Sun, R., Sheng, H., Yin, K., Pan, Y., Jiménez, R. E., Chen, S., Cui, X., Zou, Z., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.06.024 · Cited by 58
Transcriptional regulation of gene expression during osmotic stress responses by the mammalian target of rapamycin
Ortells, M. C., Morancho, B., Drews‐Elger, K., Viollet, B., Laderoute, K. R., López‐Rodríguez, C., & Aramburu, J. F. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks038 · Cited by 56
“Energy stress in general causes the increase in the intracellular [AMP]/ [ATP] ratio and engages the AMP-activated kinase AMPK, which phosphorylates and activates TSC2 (24).”
BackgroundInfluential
Sestrin2–AMPK activation protects mitochondrial function against glucose deprivation-induced cytotoxicity
Seo, K., Ki, S. H., & Shin, S. M. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.03.003 · Cited by 57
Role of MnSOD and p66shc in Mitochondrial Response to p53
Pani, G., & Galeotti, T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3499 · Cited by 55
“Although in part speculative, this possibility is supported by the ﬁnding that p53 inhibits mTOR, a major effector of growth factor signaling, through sestrins, although a redox mechanism for this action has not been demonstrated (12).”
Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells
Ibáñez-Cabellos, J. S., Aguado, C., Pérez‐Cremades, D., García‐Giménez, J. L., Bueno‐Betí, C., García-López, E., Mateo, C. R., Novella, S., Hermenegildo, C., & Pallardó, F. V. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.07.010 · Cited by 55
“To study the relationship between apoptosis and autophagy, we evaluated the levels of the anti-apoptotic protein Bcl-2, the pro-apoptotic protein Bax, and the key regulator p53, which regulates both autophagy and apoptosis by either activating Sestrin2 or Bax, respectively [35].”
Background
The GATOR2–mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation
Kowalsky, A. H., Namkoong, S., Mettetal, E., Park, H., Kazyken, D., Fingar, D. C., & Lee, J. H. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010857 · Cited by 57
Protein lysine acetylation in cellular function and its role in cancer manifestation
Arif, M., Senapati, P., Shandilya, J., & Kundu, T. K. (2010) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2010.10.002 · Cited by 58
SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes
Tajima, K., Yae, T., Javaid, S., Tam, O. H., Comaills, V., Morris, R. T., Wittner, B. S., Liu, M., Engstrom, A., Takahashi, F., et al. (2015) · Nature Communications · doi:10.1038/ncomms9257 · Cited by 54
Understanding the mTOR signaling pathway via mathematical modeling
Sulaimanov, N., Klose, M., Busch, H. S., & Boerries, M. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1379 · Cited by 54
“DNA damage downregulates mTORC1 via p53-dependent transcription of Sestrin1/2, which activates AMPK and thus leads to TSC1/2 activation and mTORC1 inactivation.(30) Less clear, but independent from TSC1/2 is the activation of mTORC1 by amino acids.”
Background
Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury
Jegal, K. H., Park, S. M., Cho, S. S., Byun, S. H., Ku, S., Kim, S. C., Ki, S. H., & Cho, I. J. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.04.010 · Cited by 54
Sestrins as a Therapeutic Bridge between ROS and Autophagy in Cancer
Sánchez‐Álvarez, M., Strippoli, R., Donadelli, M., Bazhin, A. V., & Cordani, M. (2019) · Cancers · doi:10.3390/cancers11101415 · Cited by 52
“and Prxs (through mechanisms poorly identified) [37,56,64].”
Influential
DNA Damage Response and Metabolic Reprogramming in Health and Disease
Chatzidoukaki, O., Goulielmaki, E., Schumacher, B., & Garinis, G. A. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.06.018 · Cited by 58
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
“Activated p53 also promotes the phosphorylation and activation of 5′-AMP-activated protein kinase catalytic subunit alpha (AMPKα) via SESTRIN1/2 (10).”
Background
The Role of Retinal Pigment Epithelial Cells in Age-Related Macular Degeneration: Phagocytosis and Autophagy
Si, Z., Zheng, Y., & Zhao, J. (2023) · Biomolecules · doi:10.3390/biom13060901 · Cited by 61
p53 Strikes mTORC1 by Employing Sestrins
Hay, N. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.08.010 · Cited by 52
AMP-activated Protein Kinase Antagonizes Pro-apoptotic Extracellular Signal-regulated Kinase Activation by Inducing Dual-specificity Protein Phosphatases in Response to Glucose Deprivation in HCT116 Carcinoma
Kim, M., Park, I. J., Yun, H., Kang, I., Choe, W., Kim, S. S., & Ha, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.085456 · Cited by 53
Redox Control and Interplay Between p53 Isoforms: Roles in the Regulation of Basal p53 Levels, Cell Fate, and Senescence
Hafsi, H., & Hainaut, P. L. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3771 · Cited by 60
“Other potential antioxidant products include two p53-regulated sestrins, PA26 and Hi95 (encoded by SESN1 and SESN2, respectively), which are essential for regeneration of overoxidized peroxiredoxins (5, 6), the enzymes involved in the decomposition of hydrogen peroxide3.”
Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling
Yang, K., Xu, C., Zhang, Y., He, S., & Li, D. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00728 · Cited by 53
“Interestingly, Sestrin2 has long been known to inhibit mTORC1 signaling and promote AMPK signaling (21, 22, 35).”
Background
Sestrins increase in patients with coronary artery disease and associate with the severity of coronary stenosis
Ye, J., Wang, M., Xu, Y. Q., Liu, J., Jiang, H., Wang, Z., Lin, Y., & Wan, J. (2017) · Clinica Chimica Acta · doi:10.1016/j.cca.2017.07.020 · Cited by 53
Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
Mrakovcic, M., Kleinheinz, J., & Fröhlich, L. F. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091883 · Cited by 54
“Target genes in this context are on the one hand TSC2 and on the other hand AMPK or sestrins 1 and 2 that are AMPK activators; their expression/activation finally results in decreased expression of mTOR activity responsible for promoting the autophagic process [217].”
Background
Free radical biology and medicine
(2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00480-5 · Cited by 53

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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