Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling

Abstract

The tumor suppressor p53 protects organisms from most types of cancer through multiple mechanisms. The p53 gene encodes a stress-activated transcriptional factor that transcriptionally regulates a large set of genes with versatile functions. These p53-activated genes mitigate consequences of stress regulating cell viability, growth, proliferation, repair, and metabolism. Recently, we described a novel antioxidant function of p53, which is important for its tumor suppressor activity. Among the many antioxidant genes activated by p53, Sestrins (Sesns) are critical for suppression of reactive oxygen species (ROS) and protection from oxidative stress, transformation, and genomic instability. Sestrins can regulate ROS through their direct effect on antioxidant peroxiredoxin proteins and through the AMP-activated protein kinase-target of rapamycin signaling pathway. The AMP-activated protein kinase-target of rapamycin axis is critical for regulation of metabolism and autophagy, two processes associated with ROS production, and deregulation of this pathway increases vulnerability of the organism to stress, aging, and age-related diseases, including cancer. Recently, we have shown that inactivation of Sestrin in fly causes accumulation of age-associated damage. Hence, Sestrins can link p53 with aging and age-related diseases.

FIG. 1.

Regulation of intracellular processes by p53. Tumor suppressor p53 activated by different stress stimuli regulates expression of two sets of genes depending on the nature, level, and durability of the stress. One set of genes involved in regulation of cell cycle, DNA repair, metabolism, and autophagy are activated early and responsible for support of cell viability and integrity, whereas the set of pro-oxidant and proapoptotic genes are activated by sustained and more severe stress.

FIG. 2.

Regulation of intracellular ROS. ROS, the signaling molecules and source of oxidative stress in the cell, are produced through exogenous stimuli exposure (H₂O₂, UV light, and ionizing radiation), as by-products of mitochondrial metabolism, and by several enzymes. In normal cells ROS accumulation is tightly controlled by antioxidant enzymes and some nonenzymatic systems. ROS, reactive oxygen species.

FIG. 3.

Regulation of p53 by oxidative stress. p53 is activated by oxidative stress through phosphorylation by kinases that are activated by ROS, such as ATM and AMPK. AMPK, AMP-activated protein kinase; ATM, ataxia telangiectasia mutated.

FIG. 4.

Regulation of ROS by p53. Under low stress conditions p53 regulates expression of antioxidant genes, which protect from oxidative stress. On the contrary, severe and sustainable stress activates pro-oxidant genes, which facilitate cell death.

FIG. 5.

Prx cycle. During enzymatic cycles of Prxs involved in peroxide decomposition, catalytic cysteine is oxidized to SOH group and then resolved by another Cys-SH through the formation of a S-S bridge. Under oxidative burst, SOH groups can be overoxidized to SO₂H, which is reduced by sulfiredoxins and Sestrins. Cys, cysteines; Prx, peroxiredoxin; Sesn, Sestrin.

FIG. 6.

Regulation of the mTOR signaling pathway by insulin and growth factors. Insulin/IGF1 activates PI3K through the recruitment and phosphorylation of IRS1. PI3K generates PIP3 [PtdIns(3,4,5)P3] from PIP2 [PtdIns(4,5)P2] through the recruitment of PDK1 to the cytoplasmic membrane, which stimulates AKT phosphorylation by this kinase. Another AKT kinase is TORC2, regulated through a yet to be defined mechanism. AKT phosphorylates and inhibits GAP activity of TSC2, leading to Rheb inhibition and mTORC1 suppression. IGF1, insulin-like growth factor 1; IRS1, insulin receptor substrate 1; mTOR, mammalian target of rapamycin; PDK, phosphoinositide-dependent protein kinase; PI3K, phosphatidylinositol-3-kinase; PIP, phosphatidylinositol phosphate; Rheb, Ras homolog enriched in brain; TSC2, tuberoses scleroses complex 2.

FIG. 7.

Regulation of mTOR pathway by Sestrins. Sestrins, induced by many stress insults through p53, interact with the TSC1:TSC2 complex and activate AMPK. This results in TSC2 phosphorylation and stimulation of TSC2 GAP activity, followed by inhibition of TORC1 and TORC1-dependent processes.

FIG. 8.

Role Sestrins in aging. Sestrins activated by various stresses in a p53- or forkhead transcription factor-dependent manner regulate mTOR signaling, resulting in protection from aging-related dysfunctions.