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p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
Open accessAbstract
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, p53 uses two direct target genes, SESN1 and SESN2, to block mTOR and to repress mRNA translation.211, 215”
From Census and evaluation of p53 target genes (2017) · cites this paper as [211]
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“P53 can further block mTOR activity through its direct target genes SESN1 and SESN2.211”
From Census and evaluation of p53 target genes (2017) · cites this paper as [211]
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“Sestrins are able to bind AMPK activating it and, by this mechanism, repress mTORC1 activity (Budanov and Karin, 2008).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Budanov and Karin, 2008
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“In addition, the tumor suppressor p53 has been demonstrated to activate AMPK under oxidative and genotoxic stress (Budanov and Karin, 2008).”
BackgroundMitochondrial Dysfunction in Age‐Related Metabolic Disorders
Natarajan, V., Chawla, R., Mah, T. K. L., Vivekanandan, R., Tan, S., Sato, P. Y., & Mallilankaraman, K. B. (2020) · PROTEOMICS · doi:10.1002/pmic.201800404 · Cited by 83
Solanki, S. A., Sanchez, K., Ponnusamy, V., Kota, V., Bell, H. N., Cho, C., Kowalsky, A. H., Green, M., Lee, J. H., & Shah, Y. M. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.11.014 · Cited by 83
TP53 and MTOR crosstalk to regulate cellular senescence
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“One such TP53-responsive protein is sestrin 2, which can inhibit MTOR [10] and hence induce autophagy [11, 12].”
BackgroundThe REST remodeling complex protects genomic integrity during embryonic neurogenesis
Nechiporuk, T., McGann, J. C., Müllendorff, K., Hsieh, J., Wurst, W., Floß, T., & Mandel, G. (2016) · eLife · doi:10.7554/elife.09584 · Cited by 81
“Loss of REST function alone is responsible for DNA damage Activation of the p53-pro-apoptotic pathway is often initiated due to genotoxic stress (Ko and Prives, 1996; Levine, 1997; Budanov and Karin, 2008; Elledge and Zhou, 2000).”
BackgroundMethodResultInfluentialNapoli, M., & Flores, E. R. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.384 · Cited by 80
“…(4) upregulation of several antioxidant factors, such as aldehyde dehydrogenase 4 (ALDH4; Yoon et al, 2004), sestrin-1 and -2 (SESN1 and SESN2) (Budanov and Karin, 2008), and tumour protein p53 inducible nuclear protein 1 (TP53INP1; Cano et al, 2009); and (5) repression of pro-oxidant genes…”
BackgroundDuszka, K., Gregor, A., Guillou, H., König, J. S., & Wahli, W. (2020) · Cells · doi:10.3390/cells9071708 · Cited by 86
The Evolving, Multifaceted Roles of Autophagy in Cancer
Liu, J., & Debnath, J. (2016) · Advances in cancer research · doi:10.1016/bs.acr.2016.01.005 · Cited by 82
Retrograde signaling from autophagy modulates stress responses
Simon, H., Friis, R. R., Tait, S. W. G., & Ryan, K. M. (2017) · Science Signaling · doi:10.1126/scisignal.aag2791 · Cited by 79
Hormesis does not make sense except in the light of TOR-driven aging
Blagosklonny, M. V. (2011) · Aging · doi:10.18632/aging.100411 · Cited by 83
“p53-inducing stresses DNA damage induces p53, which is known to inhibit mTOR pathway both upstream and downstream of mTOR [187-197].”
BackgroundReciprocity in ROS and autophagic signaling
Wible, D. J., & Bratton, S. B. (2017) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2017.10.006 · Cited by 83
The Emerging Role of Sestrin2 in Cell Metabolism, and Cardiovascular and Age-Related Diseases
Wanqing, S., Wang, Y., Yang, Z., & Quan, N. (2020) · Aging and Disease · doi:10.14336/ad.2019.0320 · Cited by 82
“Sesn2 promotes the metabolic adaptation of cells in response to various insults and mediates genotoxic stress-induced activation of AMPK and the suppression of mTORC1 [10].”
BackgroundInfluentialHe, T., Li, W., Song, Y., Li, Z., Tang, Y., Zhang, Z., & Yang, G. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01987-y · Cited by 80
“Sestrin2 can suppress mTOR signaling by activating AMPK and tuberous sclerosis protein complex 2 (TSC2) phosphorylation during stress [41, 42].”
BackgroundStimulation of mTORC1 with L-leucine Rescues Defects Associated with Roberts Syndrome
Xu, B., Lee, K. K., Zhang, L., & Gerton, J. L. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003857 · Cited by 84
“In some cancer cell lines, p53 activation triggers downregulation of the mTOR pathway [68,69], but p53 and mTOR are not connected in all types of cells [55,70].”
Conserved regulators of Rag GTPases orchestrate amino acid-dependent TORC1 signaling
Powis, K., & VIRGILIO, C. D. (2016) · Cell Discovery · doi:10.1038/celldisc.2015.49 · Cited by 80
Mi, D., Carr, C. B., Georgala, P. A., Huang, Y.-T., Manuel, M. N., Jeanes, E. C., Niisato, E., Sansom, S. N., Livesey, F. J., Theil, T., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.012 · Cited by 78
Xia, J., Zeng, W., Xia, Y., Wang, B., Xu, D., Liu, D., Kong, M. G., & Dong, Y. (2018) · Journal of Biophotonics · doi:10.1002/jbio.201800046 · Cited by 80
Cordani, M., Butera, G., Dando, I., Torrens‐Mas, M., Butturini, E., Pacchiana, R., Oppici, E., Cavallini, C., Gasperini, S., Tamassia, N., et al. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0288-2 · Cited by 77
TP53 Status and Response to Treatment in Breast Cancers
Varna, M., Bousquet, G., Plassa, L., Bertheau, P., & Janin, A. (2011) · BioMed Research International · doi:10.1155/2011/284584 · Cited by 87
“Under stress, p53 can activate its target gene in the nucleus, such as AMPK β1 and β2 (AMP-activated protein kinase) [28], DAPK-1 (deathassociated protein kinase1), and DRAM (damage-regulated autophagy modulator) [29].”
BackgroundLi, H., Liu, S., Yuan, H., Niu, Y., & Fu, L. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.03.023 · Cited by 78
The Architecture of the Rag GTPase Signaling Network
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“Finally, Sestrins are also stress-inducible proteins that inhibit TORC1 through the AMP-activated protein kinase (AMPK) and the TSC complex even under amino acid-replete conditions [114,115].”
BackgroundMetformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities
Pulito, C., Mori, F., Sacconi, A., Goeman, F., Ferraiuolo, M. A., Pasanisi, P., Campagnoli, C., Berrino, F., Fanciulli, M., Ford, R. J., et al. (2017) · Cell Discovery · doi:10.1038/celldisc.2017.22 · Cited by 75
Sestrins at the Interface of ROS Control and Autophagy Regulation in Health and Disease
Cordani, M., Sánchez‐Álvarez, M., Strippoli, R., Bazhin, A. V., & Donadelli, M. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/1283075 · Cited by 76
“SESN1 and SESN2 are negative regulators of mTOR signalling through the activation of AMPK and TSC2 phosphorylation in a p53-dependent manner, and this negative regulation is required for mTORC1 signalling suppression upon DNA damage [58].”
Programmed cell death, redox imbalance, and cancer therapeutics
Dai, X., Wang, D., & Zhang, J. (2021) · APOPTOSIS · doi:10.1007/s10495-021-01682-0 · Cited by 78
PAD4 and Its Inhibitors in Cancer Progression and Prognosis
Zhu, D., Lu, Y., Wang, Y., & Wang, Y. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14112414 · Cited by 83
“Mechanistically, this novel pan-PAD inhibitor suppressed H3 citrullination and activated p53 target gene expression, including SESN2, thereby inhibiting the downstream mTORC1 signaling pathway and interfering with autophagy to inhibit the proliferation of cancer cells [111,308].”
Mutant p53 as a Regulator and Target of Autophagy
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Autophagy regulation in cancer development and therapy.
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Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine
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“MnSOD p53 target gene (activator RE) Antioxidant enzyme (86) PGM p53 target gene (inhibitor RE) Glycolytic enzyme, converts 3PG into 2PG (100, 208) p53R2 p53 target gene (activator RE) Contributes to maintenance=biogenesis of mitochondria (15) PTGES (PIG12) p53 target gene (activator RE) Prostaglandin-isomerizing and…”
InfluentialRole of autophagy in head and neck cancer and therapeutic resistance
Sannigrahi, M. K., Singh, V., Sharma, R., Panda, N., & Khullar, M. (2014) · Oral Diseases · doi:10.1111/odi.12254 · Cited by 76
Autophagy: A New Mechanism of Prosurvival and Drug Resistance in Multiple Myeloma
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“One of themechanisms bywhich p53 downregulates mTOR is the activation of AMPK (positive regulator of autophagy) through the transcriptional regulation of Sestrins 1 and 2 [52].”
BackgroundAutophagy is associated with chemoresistance in neuroblastoma
Belounis, A., Nyalendo, C., Gall, R. L., Imbriglio, T. V., Mahma, M., Teira, P., Beaunoyer, M., Cournoyer, S., Haddad, É., Vassal, G., et al. (2016) · BMC Cancer · doi:10.1186/s12885-016-2906-9 · Cited by 80
“On the other hand, class III PI3K in conjunction with Beclin 1 positively regulates autophagy [18, 19].”
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The p53-induced Gene Ei24 Is an Essential Component of the Basal Autophagy Pathway
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“Ei24 is highly induced by p53 in various cell types. p53 induces autophagy activity by inhibiting mTOR activity and also by up-regulating the lysosomal protein DRAM (29, 30).”
BackgroundISG20L1 is a p53 family target gene that modulates genotoxic stress-induced autophagy
Eby, K. G., Rosenbluth, J. M., Mays, D. J., Marshall, C. B., Barton, C. E., Sinha, S., Johnson, K. N., Tang, L., & Pietenpol, J. A. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-95 · Cited by 74
Regulation of metabolic health and aging by nutrient-sensitive signaling pathways
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“Lysosomal recruitment of TSC2 is a universal response to cellular stress.”
BackgroundInfluentialDiscovery of NV-5138, the first selective Brain mTORC1 activator
Sengupta, S., Giaime, E., Narayan, S., Hahm, S., Howell, J., O’Neill, D., Vlasuk, G. P., & Saiah, E. (2019) · Scientific Reports · doi:10.1038/s41598-019-40693-5 · Cited by 72
Metadata
- Authors
- Budanov, A. V., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Karin, Michael
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 134
- Issue
- 3
- Pages
- 451-460
- ISSN
- 0092-8674 (ISSN-L)
- 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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