p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling

by: Andrei V Budanov, Michael Karin

Cell, Vol. 134, No. 3. (8 August 2008), pp. 451-460.

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Abstract

Summary 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.

@article{citeulike:3101424, abstract = {Summary 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.}, author = {Budanov, Andrei V. and Karin, Michael }, citeulike-article-id = {3101424}, doi = {http://dx.doi.org/10.1016/j.cell.2008.06.028}, journal = {Cell}, keywords = {dna-damage, dna-repair, mtor, p53}, month = {August}, number = {3}, pages = {451--460}, posted-at = {2008-08-08 17:04:55}, priority = {2}, title = {p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling}, url = {http://dx.doi.org/10.1016/j.cell.2008.06.028}, volume = {134}, year = {2008} }

RIS record

TY - JOUR ID - citeulike:3101424 L3 - citeulike-article-id:3101424 N2 - Summary 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. IS - 3 JF - Cell EP - 460 TI - p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling VL - 134 SP - 451 KW - dna-damage KW - dna-repair KW - mtor KW - p53 AU - Budanov, Andrei AU - Karin, Michael PY - 2008/08/08/ UR - http://dx.doi.org/10.1016/j.cell.2008.06.028 ER -

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