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
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Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,351

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Background
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Chen, N., & Debnath, J. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.12.034 · Cited by 233
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Background
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Background
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Background
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Background
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“85).”
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Background
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Background
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Background
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Background
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Background
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Background
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BackgroundInfluential
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Wang, W., & Guan, K. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01980.x · Cited by 167
“The ability of p53 to inhibit mTOR signalling is thought to be essential to the inhibition of cell growth and proliferation during genotoxic stress (Lee et al. 2007a, Budanov & Karin 2008).”
Background
Nucleolar Disruption in Dopaminergic Neurons Leads to Oxidative Damage and Parkinsonism through Repression of Mammalian Target of Rapamycin Signaling
Rieker, C., Engblom, D., Kreiner, G., Domanskyi, A., Schober, A., Stotz, S., Neumann, M., Yuan, X., Grummt, I., Schütz, G., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0590-10.2011 · Cited by 169
“…of stress signals such as low levels of ribosome biogenesis, hypoxia, or DNA damage, p53 may set a negative feedback on mTOR signaling by activating AMP-activated protein kinase and/or by the synthesis of the protein REDD1 (Ellisen et al., 2002; Budanov and Karin, 2008; DeYoung et al., 2008).”
Background
Gene expression following ionising radiation: Identification of biomarkers for dose estimation and prediction of individual response
Kabacik, S., Mackay, A. G., Tamber, N., Manning, G., Finnon, P., Paillier, F., Ashworth, A., Bouffler, S. D., & Badie, C. (2010) · International Journal of Radiation Biology · doi:10.3109/09553002.2010.519424 · Cited by 162
“SESN1 is an anti-oxidant gene activated through p53 transcriptional programme as are CDKN1A and GADD45A (Budanov and Karin 2008).”
Background
DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence
Leontieva, O. V., & Blagosklonny, M. V. (2010) · Aging · doi:10.18632/aging.100265 · Cited by 163
“The tumor suppressor p53 inhibits the mTOR pathway upstream [21-24] and downstream [25, 26] of mTOR.”
Background
Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals
Segalés, J., Perdiguero, E., Serrano, A. L., Sousa-Victor, P., Ortet, L., Jardí, M., Budanov, A. V., Garcia-Prat, L., Sandri, M., Thomson, D. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13832-9 · Cited by 153
Self-citation
Ginsenoside F2 induces apoptosis accompanied by protective autophagy in breast cancer stem cells
Mai, T. T., Moon, J., Song, Y., Viet, P. Q., Phuc, P. V., Lee, J. M., Yi, T., Cho, M., & Cho, S. K. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.01.045 · Cited by 161
Modulating autophagy in cancer therapy: Advancements and challenges for cancer cell death sensitization
Bhat, P., Kriel, J., Priya, B. S., Basappa, B., Shivananju, N. S., & Loos, B. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.11.021 · Cited by 159
Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress
Wu, S., Wu, Y., Wu, T.-P., & Wei, Y. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.10.034 · Cited by 164
The role of tumor suppressor p53 in the antioxidant defense and metabolism
Budanov, A. V. (2014) · Subcellular Biochemistry · doi:10.1007/978-94-017-9211-0_18 · Cited by 157
“…and AMPKβ1 (Budanov, 2011; Levine et al., 2006). p53 also stimulates phosphorylation of AMPKα subunits on T172, required for mTORC1 inhibition (Feng et al., 2005). p53-activated Sesn1 and Sesn2 play a major role in activation of AMPK phosphorylation in response to p53 (Budanov and Karin, 2008).”
BackgroundInfluentialSelf-citation
Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death
Ben‐Sahra, I., Dirat, B., Laurent, K., Puissant, A., Auberger, P., Budanov, A. V., Tanti, J., & Bost, F. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.157 · Cited by 157
“Previous studies have shown that Sesn2 expression inhibits cell growth and proliferation in response to a genotoxic stress.(15,36) However, in the same study, the expression of Sesn2 protected MCF-7 cells against ischemia/low glucose and H2O2.”
BackgroundInfluentialSelf-citation
The evolution of the TOR pathway and its role in cancer
Beauchamp, E. M., & Platanias, L. C. (2012) · Oncogene · doi:10.1038/onc.2012.567 · Cited by 158
Unraveling the AMPK-SIRT1-FOXO Pathway: The In-Depth Analysis and Breakthrough Prospects of Oxidative Stress-Induced Diseases
Guan, G., Chen, Y., & Dong, Y. (2025) · Antioxidants · doi:10.3390/antiox14010070 · Cited by 175
“In the cytoplasm, p53 inhibits mTOR activity by interacting with TSC2, a key upstream regulator of mTOR [101].”
Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains
Kim, H., An, S., Ro, S., Teixeira, F., Park, G. J., Kim, C., Cho, C., Kim, J.-S., Jakob, U., Lee, J. H., et al. (2015) · Nature Communications · doi:10.1038/ncomms10025 · Cited by 160
Exploring the multiple roles of guardian of the genome: P53
Feroz, W., & Sheikh, A. M. A. (2020) · Egyptian Journal of Medical Human Genetics · doi:10.1186/s43042-020-00089-x · Cited by 172
“In contrast, under genomic stress P53 can activate AMPK via sestrin 1 and sestrin 2, leading to inhibition of mTOR and thus arrest of cell growth and proliferation [115].”
Background
Lysosomes in senescence and aging
Tan, J. X., & Finkel, T. (2023) · EMBO Reports · doi:10.15252/embr.202357265 · Cited by 178
“…complex, normally activated on lysosomes, is often inhibited by cell stress, such as nutrient starvation, lysosomal perturbation, DNA damage, hypoxia, oxidative stress, and ER stress (Budanov & Karin, 2008; Qin et al , 2010; Sengupta et al , 2010; Aramburu et al , 2014; Heberle et al , 2015).”
Autophagy as a target for cancer therapy: new developments
Nawrocki, S. T., Carew, & Kelly, K. (2012) · Cancer Management and Research · doi:10.2147/cmar.s26133 · Cited by 156
Homeostatic functions of the p53 tumor suppressor: Regulation of energy metabolism and antioxidant defense
Olovnikov, I. A., Kravchenko, J. E., & Chumakov, P. M. (2008) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.11.005 · Cited by 156
“Another mechanism involves activation of AMPK by p53-modulated Sesn1 and Sesn2 [59].”
New Insights into the Link Between DNA Damage and Apoptosis
Zio, D. D., Cianfanelli, V., & Cecconi, F. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4938 · Cited by 166
“…genes, such as AMP-activated protein kinase subunits b 1 and b 2 ( AMPK-b 1/2 ), tuberous sclerosis protein 2 ( TSC2 ), phosphatase and tensin holomog ( PTEN ), damage-regulated autophagy modulator ( DRAM ), sestrin1 and 2 ( Sesn1/2 ), and Unc-51-like kinase 1 ( ULK1 ) (11, 23, 29, 31).”
Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases
Pasha, M., Eid, A. H., Eid, A. A., Gorin, Y. C., & Munusamy, S. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/3296294 · Cited by 153
“(ii) Activation of AMPK pathway [1, 3, 8] (iii) Downregulation of mTOR pathway [1, 3, 6, 9]”
Influential
mTORC1 pathway in DNA damage response
Ma, Y., Vassetzky, Y. S., & Dokudovskaya, S. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.06.011 · Cited by 157
Reactive oxygen species regulation of autophagy in cancer: Implications for cancer treatment
Li, L., Ishdorj, G., & Gibson, S. B. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.07.011 · Cited by 154
DNA damage related crosstalk between the nucleus and mitochondria
Saki, M. R., & Prakash, A. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.11.050 · Cited by 153
A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol
Sajish, M., & SCHIMMEL, P. R. (2014) · Nature · doi:10.1038/nature14028 · Cited by 153
“g, Only the full-length TyrRS (1-528) and none of the various fragments of TyrRS (mini-TyrRS (1-364), ΔN-TyrRS (228-528) or the C-domain (328-528)) interacts with PARP-1.”
Background
p53 and metabolism: from mechanism to therapeutics
Simabuco, F. M., Morale, M. G., Pavan, I. C. B., Morelli, A. P., Silva, F. R., & Tamura, R. E. (2018) · Oncotarget · doi:10.18632/oncotarget.25267 · Cited by 159
“AMPK phosphorylation can also be induced by Sestrins [129, 195, 196], which have been observed to be increased by mutant p53 knockdown [194]. mTOR activity can also be modulated by EGFR, it has also been shown that p53R280K has an increased EGFR signaling [197].”
The regulation of cellular metabolism by tumor suppressor p53
Liang, Y., Liu, J., & Feng, Z. (2013) · Cell & Bioscience · doi:10.1186/2045-3701-3-9 · Cited by 154
“p53 activates AMPK through its induction of AMPK-β and Sestrins 1/2, leading to the down-regulation of the mTOR activity [69,70].”
Background
Mammalian Target of Rapamycin: Hitting the Bull′s‐Eye for Neurological Disorders
Chong, Z. Z., Shang, Y., Zhang, L., Wang, S., & Maiese, K. (2010) · Oxidative Medicine and Cellular Longevity · doi:10.4161/oxim.3.6.14787 · Cited by 149
EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains
Collier, M. D., Sungalee, S., Zufferey, M., Tavernari, D., Katanayeva, N., Battistello, E., Mina, M., Douglass, K. M., Rey, T., Raynaud, F., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0338-y · Cited by 150
Calcium signaling alterations, oxidative stress, and autophagy in aging
Ureshino, R. P., Rocha, K. K., Lopes, G. S., Bincoletto, C., & Smaili, S. S. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5777 · Cited by 143
“Damage-regulated autophagy modulator, a phylogenetical lysosomal protein (31), the b 1 and b 2 subunits of AMPK (adenosine monophosphate-activated protein kinase) (44), and sestrin 1 and sestrin 2 (19), which also activate AMPK, are direct targets of p53.”
Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice
Komarova, E. A., Antoch, M. P., Novototskaya, L. R., Chernova, O. B., Paszkiewicz, G., Leontieva, O. V., Blagosklonny, M. V., & Gudkov, A. V. (2012) · Aging · doi:10.18632/aging.100498 · Cited by 145
Quercetin regulates the sestrin 2-AMPK-p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner
Kim, G. T., Lee, S. H., Kim, J., & Kim, Y. M. (2014) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2014.1658 · Cited by 146
“Previous studies have indicated that sestrin 2 expression in cancer cells suppresses cell growth and proliferation by leading to the negative control of mTOR through AMPK α 1 phosphorylation (8,9).”
Genome-wide analysis of glucocorticoid receptor-binding sites in myotubes identifies gene networks modulating insulin signaling
Kuo, T., Lew, M. J., Mayba, O., Harris, C. A., Speed, T. P., & Wang, J.-C. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1111334109 · Cited by 148
“Sesn 1 (24), Ddit4 (15), and Depdc6 (25) inhibit mTOR.”
Fangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells
Wang, N., Pan, W., Zhu, M., Zhang, M., Hao, X.-J., Liang, G., & Feng, Y. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01349.x · Cited by 145
“Recent studies found that removal of sestrin2 could suppress autophagy induced by various stimulators, where activation of AMPK signalling and inhibition of mTOR are involved as the key mechanisms (Budanov and Karin, 2008; D’Amelio and Cecconi, 2009).”
Background
The role of LKB1 and AMPK in cellular responses to stress and damage
Alexander, A., & Walker, C. L. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.03.010 · Cited by 145
“A second DNA damage-induced pathway for AMPK activation involves p53 [33].”
Background
mTORC1 signaling: what we still don't know
Wang, X., & Proud, C. G. (2010) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjq038 · Cited by 150
“Conversely, there is evidence that p53 negatively regulates mTORC1 signaling, perhaps through sestrins, which are encoded by p53 target genes (Horton et al., 2002; Budanov and Karin, 2008).”
Background
Molecular links between cellular senescence, longevity and age-related diseases – a systems biology perspective
Tăcutu, R., Budovsky, A., Yanai, H., & Fraifeld, V. E. (2011) · Aging · doi:10.18632/aging.100413 · Cited by 146
“A common event in the stressed cells is a down-regulation of insulin/IGF1-AktmTOR axis by up-regulated p53 [58-64].”
Background
The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth ControlPreprint
Hindupur, S. K., González, A., & Hall, M. N. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019141 · Cited by 147
“Active AMPK leads to activation of TSC2 and a decrease in mTORC1 activity (Budanov and Karin 2008).”
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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