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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Soontornniyomkij, V., Soontornniyomkij, B., Moore, D. J., Gouaux, B. D., Masliah, E., Tung, S., Vinters, H. V., Grant, I., & Achim, C. L. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9357-0 · Cited by 24
“Sestrin-2 has been shown to play a key role in p53- dependent antioxidant defenses (Budanov and Karin 2008; Budanov et al. 2004).”
Che-1/AATF: A Critical Cofactor for Both Wild-Type- and Mutant-p53 Proteins
Bruno, T., Iezzi, S., & Fanciulli, M. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00034 · Cited by 23
“For instance, p53 inhibits the kinase mTOR, in response to DNA damage through sestrin1 and 2 activation (35).”
Background
SAHA and cisplatin sensitize gastric cancer cells to doxorubicin by induction of DNA damage, apoptosis and perturbation of AMPK-mTOR signalling
Seah, K. S., Loh, J. Y., Nguyen, T. T. T., Tan, H. L., Hutchinson, P. E., Lim, K. K., Dymock, B. W., Long, Y. C., Lee, E. J. D., Shen, H., et al. (2018) · Experimental Cell Research · doi:10.1016/j.yexcr.2018.06.029 · Cited by 23
Effect of Aerobic Exercise on Oxidative Stress and Inflammatory Response During Particulate Matter Exposure in Mouse Lungs
So, B., Park, J.-H., Jang, J.-H., Lim, W., Imdad, S., & Kang, C. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.773539 · Cited by 26
“The antioxidant function of Sestrin2 promotes the activation of AMPKα (Budanov and Karin, 2008).”
BackgroundInfluential
Exercise protects intestinal epithelial barrier from high fat diet- induced permeabilization through SESN2/AMPKα1/HIF-1α signaling
Yu, C., Liu, S., Niu, Y., & Fu, L. (2022) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2022.109059 · Cited by 23
Sestrin2 attenuates renal damage by regulating Hippo pathway in diabetic nephropathy
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Spatiotemporal roles of AMPK in PARP-1- and autophagy-dependent retinal pigment epithelial cell death caused by UVA
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“The underlying mechanisms include AMPK activation [10] and p53-dependent gene transcription of AMPK and Sestrin 1/2 [13, 14].”
Background
Hyperphosphatemia induces cellular senescence in human aorta smooth muscle cells through integrin linked kinase (ILK) up-regulation
Troyano, N., Avila, M. D. N., Mora, I., Naves‐Díaz, M., Carrillo‐López, N., Sosa, P., Rodrı́guez-Puyol, D., Olmos, G., & Ruiz‐Torres, M. P. (2015) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2015.10.001 · Cited by 24
A herpesvirus kinase that masquerades as Akt
Chuluunbaatar, U., & Mohr, I. (2011) · Cell Cycle · doi:10.4161/cc.10.13.16242 · Cited by 23
Antagonistic role of natural compounds in mTOR-mediated metabolic reprogramming
Cerella, C., Gaigneaux, A., Dicato, M. A., & Diederich, M. F. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.02.008 · Cited by 23
α‐tocopheryl‐phosphate regulation of gene expression in preadipocytes and adipocytes
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The DNA Binding Domain of p53 Is Sufficient To Trigger a Potent Apoptotic Response at the Mitochondria
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p53 promotes AKT and SP1-dependent metabolism through the pentose phosphate pathway that inhibits apoptosis in response to Nutlin-3a
Duan, L., Perez, R. E., Chen, L., Blatter, L. A., & Maki, C. G. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx051 · Cited by 24
Plk2 Loss Commonly Occurs in Colorectal Carcinomas but not Adenomas: Relationship to mTOR Signaling
Matthew, E. M., Yang, Z., Peri, S., Andrake, M., Dunbrack, R. L., Ross, E. A., & El‐Deiry, W. S. (2018) · Neoplasia · doi:10.1016/j.neo.2018.01.004 · Cited by 23
“Genotoxic stress may inhibit mTOR activity through up-regulation of known negative regulators PTEN (phosphatase and tensin homolog), TSC2 and AMPKβ1 (AMP-responsive protein kinase) β1 and AMPKα in a p53-dependent manner [7,8].”
Background
Phosphorylation of TSC2 by PKC-δ reveals a novel signaling pathway that couples protein synthesis to mTORC1 activity
Zhan, J., Chitta, R. K., Harwood, F. C., & Grosveld, G. C. (2019) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-019-03498-8 · Cited by 23
Non-Thermal Plasma Induces Antileukemic Effect Through mTOR Ubiquitination
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“Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove e ﬀ ective in the treatment of AML. p53 can inhibit mTOR by regulating a pathway that is used to detect nutrient deprivation, such as AMPK, and subsequently the TSC1 / TSC2 complex [81].”
Influential
A combination of AZD5363 and FH5363 induces lethal autophagy in transformed hepatocytes
Patra, T., Meyer, K., Ray, R. B., & Ray, R. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02741-1 · Cited by 26
Sestrin Proteins Protect Against Lipotoxicity-Induced Oxidative Stress in the Liver via Suppression of C-Jun N-Terminal Kinases
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“Sestrins can activate AMP-activated protein kinase (AMPK) through an interaction with its alpha subunits.(2) Sestrins also activate mechanistic target of rapamycin complex 2 (mTORC2) through a direct interaction with rapamycininsensitive companion of mTOR and GATOR2, whereas they inhibit mTORC1 by regulating GATOR2.”
Background
Sestrin2, a Regulator of Thermogenesis and Mitohormesis in Brown Adipose Tissue
Ro, S., Semple, I. A., Ho, A., Park, H., & Lee, J. H. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00114 · Cited by 24
“Sestrin2may promotemitochondrial biogenesis through activation of AMPK (7, 12, 101, 102) and subsequent upregulation of PGC-1α activity (103, 104).”
Background
Autophagy in Skeletal MusclePreprint
Franco‐Romero, A., Sandri, M., & Schiaffino, S. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041565 · Cited by 23
p53: from understanding its structure to advances in therapeutic targeting
Wang, W., Liu, X., Liu, H., Abolhassani, H., Yan, H., Zhang, H., & Wang, X. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02549-5 · Cited by 29
“116 As a p53 target gene, damage-regulated autophagy modulator (DRAM) is an effector of p53-mediated death and encodes a lysosomal protein that promotes autophagy.”
Low expression or hypermethylation of PLK2 might predict favorable prognosis for patients with glioblastoma multiforme
Xia, X., Cao, F., Yuan, X., Zhang, Q., Chen, W., Yu, Y., Xiao, H., Han, C., & Yao, S. (2019) · PeerJ · doi:10.7717/peerj.7974 · Cited by 22
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“p53 translocates to the nucleus and promotes the transcription and expression levels of sestrin1 and sestrin2, which can further stimulate autophagy via the AMPK-TSC2-mTOR pathway (6,30).”
Background
OncomiR miR-182-5p Enhances Radiosensitivity by Inhibiting the Radiation-Induced Antioxidant Effect through SESN2 in Head and Neck Cancer
Lin, M.-Y., Chang, Y., Wang, S.-Y., Yang, M., Chang, C.-H., Hsiao, M., Kitsis, R. N., & Lee, Y. (2021) · Antioxidants · doi:10.3390/antiox10111808 · Cited by 23
Autophagy-related signaling pathways in non-small cell lung cancer
Wang, J., Gong, M., Fan, X., Huang, D., Zhang, J., & Huang, C. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04280-5 · Cited by 24
“After being phosphorylated by multiple kinases under cellular stress, cytoplasmic p53 relocates to the nucleus and promotes sestrin1-2 production, which can activate autophagy via the AMPK/mTOR pathway [83].”
Background
The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
Murphy, J., Le, T. N. V., Fedorova, J., Yang, Y., Krause‐Hauch, M., Davitt, K., Zoungrana, L. I., Fatmi, M. K., Lesnefsky, E. J., Li, J., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.850538 · Cited by 23
“5XFAD and wild type (WT) (2–6 months) C57BL/6J mice were bred and supplied by our lab as the previous reports described (17–19).”
Constitutive and induced functions of the p53 gene
Zheltukhin, A. O., & Chumakov, P. M. (2010) · Biochemistry (Moscow) · doi:10.1134/s0006297910130110 · Cited by 23
RBX1-mediated ubiquitination of SESN2 promotes cell death upon prolonged mitochondrial damage in SH-SY5Y neuroblastoma cells
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Metabolic signature of squamous cell carcinoma of the head and neck: Consequences of TP53 mutation and therapeutic perspectives
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Tocotrienol-Rich Fraction (TRF) Treatment Promotes Proliferation Capacity of Stress-Induced Premature Senescence Myoblasts and Modulates the Renewal of Satellite Cells: Microarray Analysis
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“Inhibition of mTORC1 activation via the sestrin-AMPK pathway was reported to extend the lifespan of mammalia [59 – 61].”
Background
AMPK: A promising molecular target for combating cisplatin toxicities
Rashtchizadeh, N., Argani, H., Ghorbanihaghjo, A., Sanajou, D., Hosseini, V., Dastmalchi, S., & Ahmad, S. N. S. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.02.006 · Cited by 23
Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling
Wang, X., Liu, W., Zhuang, D., Hong, S., & Chen, J. (2017) · Oncotarget · doi:10.18632/oncotarget.21487 · Cited by 22
“SESN1 and SESN2 are intracellular leucine sensors and p53 target genes that restrain mTORC1 signaling [13, 14].”
Decoding the dual role of autophagy in cancer through transcriptional and epigenetic regulation
Yu, Y. S., Kim, I. S., & Baek, S. H. (2025) · FEBS Letters · doi:10.1002/1873-3468.70060 · Cited by 24
“In the nucleus, p53 induces autophagy through the regulation of genes including DRAM1 , SESN1/2 , ATG12 , and BECN1 [73,74].”
Ubiquilin Networking in Cancers
Jantrapirom, S., Piccolo, L. L., Pruksakorn, D., Potikanond, S., & Nimlamool, W. (2020) · Cancers · doi:10.3390/cancers12061586 · Cited by 22
“In particular, Sestrin1/2 then activates TSC1/2 complex and also AMP-activated protein kinase (AMPK) to promote the autophagy induction via mTOR1 inactivation [43].”
Background
Methylglyoxal induces p53 activation and inhibits mTORC1 in human umbilical vein endothelial cells
Zhang, X., Rodriguez-Niño, A., Pastene, D. O., Pallavi, P., van den Born, J., Bakker, S. J. L., Krämer, B. K., & Yard, B. A. (2021) · Scientific Reports · doi:10.1038/s41598-021-87561-9 · Cited by 22
MiR-200c-3p targets SESN1 and represses the IL-6/AKT loop to prevent cholangiocyte activation and cholestatic liver fibrosis
Song, Y., Tran, M., Wang, L., Shin, D., & Wu, J. (2021) · Laboratory Investigation · doi:10.1038/s41374-021-00710-6 · Cited by 22
“Independently of their redox activity, SESN1 inhibits expression of mTOR, thus mediating its aging-related function [19].”
ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice
Kouzu, H., Tatekoshi, Y., Chang, H.-C., Shapiro, J. S., McGee, W. A., Jesus, A. D., Ben-Sahra, I., Arany, Z., Leor, J., Chen, C., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154491 · Cited by 21
“Three studies suggest that mTORc1 inhibition by genotoxic stress is dependent on P53 (36, 38, 42).”
Background

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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