p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
Copyright policy )p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
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.
- University of California, San Diego United States
- University of California, San Diego United States
- Trinity College Dublin Ireland
570, CELL GROWTH, Sestrins, 610, Cell Cycle Proteins, AMP-Activated Protein Kinases, Protein Serine-Threonine Kinases, Tuberous Sclerosis Complex 1 Protein, Cell Line, Mice, Multienzyme Complexes, Genotoxic stress, Cell Line, Tumor, Tuberous Sclerosis Complex 2 Protein, Animals, Humans, PHOSPHORYLATION, Cancer, Biochemistry, Genetics and Molecular Biology(all), Tumor Suppressor Proteins, Nuclear Proteins, Proteins, Tumour suppression, Mice, Inbred C57BL, Ageing, Peroxidases, Health, SIGNALING, Age-related disability, Tumor Suppressor Protein p53, DNA Damage, Signal Transduction
570, CELL GROWTH, Sestrins, 610, Cell Cycle Proteins, AMP-Activated Protein Kinases, Protein Serine-Threonine Kinases, Tuberous Sclerosis Complex 1 Protein, Cell Line, Mice, Multienzyme Complexes, Genotoxic stress, Cell Line, Tumor, Tuberous Sclerosis Complex 2 Protein, Animals, Humans, PHOSPHORYLATION, Cancer, Biochemistry, Genetics and Molecular Biology(all), Tumor Suppressor Proteins, Nuclear Proteins, Proteins, Tumour suppression, Mice, Inbred C57BL, Ageing, Peroxidases, Health, SIGNALING, Age-related disability, Tumor Suppressor Protein p53, DNA Damage, Signal Transduction
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