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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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Citations
Cites
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mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509
“DNA damage induces the expression of Tsc2 and phosphatase and tensin homolog deleted on chromosome 10 (Pten), causing downregulation of the entire PI3K-mTORC1 axis (Feng et al., 2005; Stambolic et al., 2001), and activates AMPK through a mechanism that depends on the induction of Sestrin1/2 (Budanov and Karin, 2008).”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
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BackgroundBlinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163
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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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