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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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
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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)
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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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