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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Lee, S., Byun, J., Park, M., Kim, S. W., Lee, S., Kim, J., Lee, I., Choi, Y., & Park, K. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8638 · Cited by 17
“Sestrin2 suppresses mTORC1 signaling via activation of AMPK-activated protein kinase (AMPK) or inhibition of Rag GTPases (7,8).”
BackgroundResult
Sestrin2 inhibits YAP activation and negatively regulates corneal epithelial cell proliferation
Lee, J., Park, H., Cho, K. J., & Lyu, J. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0446-5 · Cited by 17
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Khalil, H., ElHady, A. A., Elawdan, K. A., Mohamed, D. D., Mohamed, D. D., Maksoud, A. I. A. E., El-Chennawi, F. A., El-Fikiy, B., & El-Sayed, I. H. (2020) · Immunological Investigations · doi:10.1080/08820139.2020.1828453 · Cited by 18
“p53 wild type (wt) cells, while their genetic depletion enhanced mTORC1 activity in p53 wt cells (Budanov and Karin 2008; Chantranupong et al. 2014; Hay 2008; Peng et al. 2014).”
Background
Mutant p53 drives the loss of heterozygosity by the upregulation of Nek2 in breast cancer cells
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“Its activation will depend on Sestrin 1 and 2, also controlled by p53 [36,43,44].”
Background
HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis
Sannigrahi, M. K., Rajagopalan, P., Lai, L., Liu, X., Sahu, V., Nakagawa, H., Jalaly, J. B., Brody, R. M., Morgan, I. M., Windle, B. E., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.159600 · Cited by 17
“Increased p53 also drives expression of sestrins (45), which mediate PGC-1 α activation by stimulating its phosphorylation by AMPK (46).”
Drugging in the absence of p53
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Evaluation of Eribulin Combined with Irinotecan for Treatment of Pediatric Cancer Xenografts
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“Sestrins 1 and 2 (SESN1/2), induced downstream of DNA-damage-induced TP53, suggest that irinotecan may suppress TORC1 activity (44), that could affect DNA damage repair (45).”
Background
Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser
Gnanapradeepan, K., Roy, S. B., Barnoud, T., Leu, J. I.-J., Good, M., Lee, J. V., Quinn, W. J., Kung, C.-P., Ahima, R. S., Baur, J. A., et al. (2020) · eLife · doi:10.7554/elife.55994 · Cited by 16
“p53 negatively regulates the mTOR pathway in part through transactivation of the target genes PTEN, TSC2, PRKAB1 and SESN1/SESN2 (Budanov and Karin, 2008; Feng et al., 2005).”
BackgroundInfluential
MiR-182/Sestrin2 affects the function of asthmatic airway smooth muscle cells by the AMPK/mTOR pathway
Xiao, Y., Zhu, H., Lei, J., Xie, J., Wu, K., Gu, W., Ma, J., wei, D., Shu, Z., & Zhao, L. (2021) · Journal of Translational Internal Medicine · doi:10.2478/jtim-2021-0033 · Cited by 16
N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells
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p53 and metabolism: Old player in a new game
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Sestrin family may play important roles in the regulation of cardiac pathophysiology
Liao, H.-H., Ruan, J., Liu, H.-J., Liu, Y., Feng, H., & Tang, Q. (2015) · International Journal of Cardiology · doi:10.1016/j.ijcard.2015.08.164 · Cited by 16
DNA damage regulates direct association of TOR kinase with the RNA polymerase II–transcribedHMO1gene
Panday, A., Gupta, A., Srinivasa, K., Xiao, L., Smith, M. D., & Grove, A. (2017) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-01-0024 · Cited by 16
“The cell-cycle arrest that accompanies unrepaired DNA damage must be coordinated with metabolic arrest, and this process requires mTORC1 (Shen et al., 2007; Budanov and Karin, 2008; Dulic, 2013).”
Background
Leucine regulates α-amylase and trypsin synthesis in dairy calf pancreatic tissue in vitro via the mammalian target of rapamycin signalling pathway
Guo, L. J., Yao, J. H., Zheng, C., Tian, H. B., Liu, Y., Liu, S. M., Cai, C., Xu, X. R., & Cao, Y. (2019) · animal · doi:10.1017/s1751731118003683 · Cited by 17
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“In addition, the mTORC1 itself was regulated by not only AMPK but by other pathways (Budanov and Karin, 2008), which could result in cell type- and contextdependent mTORC1 responses.”
Background
Maintenance BEZ235 Treatment Prolongs the Therapeutic Effect of the Combination of BEZ235 and Radiotherapy for Colorectal Cancer
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“It was previously reported that as a stress-responsive gene, Sestrin 2 inhibited mTORC1 signaling through the AMPK/TSC signaling axis [55,56].”
Background
Correlation between sestrin2 expression and airway remodeling in COPD
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“Moreover, it has also been reported that in cell culture, knockdown of sestrin2 reduced AMPK and SOD2 levels [23], and we have observed simultaneous effect during overload induced hypertrophy.”
BackgroundInfluential
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“tioxidant defense of the cell (Budanov and Karin 2008).”
BackgroundInfluential
The human ΔNp53 isoform triggers metabolic and gene expression changes that activate mTOR and alter mitochondrial function
Lin, S., Karoly, E. D., & Taatjes, D. J. (2013) · Aging Cell · doi:10.1111/acel.12108 · Cited by 16
TRIM21-driven K63-linked ubiquitination of RBM38c, as a novel interactor of BECN1, contributes to DNA damage-induced autophagy
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“Additionally, upon DNA damage, the tumor suppressor TP53 promotes autophagy by stimulating AMPK or through transcription-dependent pathways that involve mTOR inhibitors and TP53-regulated autophagy genes like DRAM1 [5, 12 – 15].”
Repression of Gurken translation by a meiotic checkpoint inDrosophilaoogenesis is suppressed by a reduction in the dose ofeIF1A
Li, W., Klovstad, M. S., & Schüpbach, T. (2014) · Development · doi:10.1242/dev.109306 · Cited by 15
“Alternatively, as some of the key regulators that mediate the inhibitory effect of DNA damage on translation in mammalian cells (such as p53) (Budanov and Karin, 2008; Cam et al., 2014) are not required by the Drosophila meiotic DNA damage checkpoint to repress Grk translation (Abdu et al.”
Background
Empirical relationships between compressive and flexural strength of concrete containing recycled asphalt material for pavement applications using different specimen configurations
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“Therefore, SESN1 and SESN2 are important IR-induced mediators of the DDR via P53 and mTOR signaling pathway [17].”
Background
E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and implications for immunotherapies
Wang, M., Zhang, Z., Li, Z., Zhu, Y., & Xu, C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1226057 · Cited by 16
Bta-miR-330 promotes bovine intramuscular pre-adipocytes adipogenesis via targeting SESN3 to activate the Akt-mTOR signaling pathway
Yang, Z., Ma, X., Zhang, D., Li, B., Gao, N., Li, X., Mei, C., & Zan, L. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.133650 · Cited by 15
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“While the sestrin family of proteins was first implicated in redox control [30,31,32], recent studies have been focusing on the role of sestrins in mTORC1 signaling.”
BackgroundInfluential
Exercising insulin sensitivity: AMPK turns on autophagy!
Dagon, Y., Mantzoros, C. S., & Kim, Y. (2015) · Metabolism · doi:10.1016/j.metabol.2015.03.002 · Cited by 16
“Interestingly, Sestrins also suppressed the mTOR signaling cascade through AMPK dependent (24) or independent pathway (25).”
Background
[Retracted] p53 suppresses stress‑induced cellular senescence via regulation of autophagy under the deprivation of serum
Sui, X., Fang, Y., Lou, H., Wang, K., ZHENG, Y., Lou, F., JIN, W., Xu, Y., Chen, W., Pan, H., et al. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2853 · Cited by 15
“…p53 is able to inhibit the mTOR pathway through a number of known p53 transcriptional targets, including AMP-activated protein kinase, tuberous sclerosis complex 2, phosphatase and tensin homolog (PTEN), and sestrins, all of which are upstream negative regulators of the mTOR pathway (30,31).”
Retracted
The guardian of the genome p53 regulates exercise‐induced mitochondrial plasticity beyond organelle biogenesis
Smiles, W. J., & CAMERA, D. M. (2017) · Acta Physiologica · doi:10.1111/apha.13004 · Cited by 15
Cестрины – шлагбаумы на путях от стресса к старению и болезням
Dalina, A. A., Kovaleva, I. E., & Budanov, A. V. (2018) · Molecular Biology · doi:10.1134/s0026898418060046 · Cited by 15
Self-citation
AMPK Activation of Apoptotic Markers in Human Breast Cancer Cell Lines with Different p53 Backgrounds: MCF-7, MDA-MB-231 and T47D Cells
El-Masry, O. S., BROWN, B. L., & Dobson, P. R. M. (2019) · Asian Pacific Journal of Cancer Prevention · doi:10.31557/apjcp.2019.20.12.3763 · Cited by 15
“On the other hand, it is activated downstream of the p53 transcription targets, sestrin 1 and 2 (Levine et al., 2006; Budanov and Karin, 2008) and the β subunit of AMPK is encoded by a p53 responsive gene (Feng et al., 2007).”
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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