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      Serine- and Threonine/Valine-Dependent Activation of PDK and Tor Orthologs Converge on Sch9 to Promote Aging


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          Dietary restriction extends longevity in organisms ranging from bacteria to mice and protects primates from a variety of diseases, but the contribution of each dietary component to aging is poorly understood. Here we demonstrate that glucose and specific amino acids promote stress sensitization and aging through the differential activation of the Ras/cAMP/PKA, PKH1/2 and Tor/S6K pathways. Whereas glucose sensitized cells through a Ras-dependent mechanism, threonine and valine promoted cellular sensitization and aging primarily by activating the Tor/S6K pathway and serine promoted sensitization via PDK1 orthologs Pkh1/2. Serine, threonine and valine activated a signaling network in which Sch9 integrates TORC1 and Pkh signaling via phosphorylation of threonines 570 and 737 and promoted intracellular relocalization and transcriptional inhibition of the stress resistance protein kinase Rim15. Because of the conserved pro-aging role of nutrient and growth signaling pathways in higher eukaryotes, these results raise the possibility that similar mechanisms contribute to aging in mammals.

          Author Summary

          Calorie restriction (CR), but also the restriction of specific components of the diet, has been known for decades to affect longevity. However, the understanding of how each component of the macronutrients affects longevity and stress resistance is poorly understood, in part because of the complexity of many of the model organisms studied. Here we studied how each amino acid and glucose cooperate to activate cell sensitizing pathways and promote aging. We identified specific amino acids in the diet that affect cellular protection and aging, describe how different pathways mediate these pro-aging effects, describe the effect of glucose and specific amino acids on the levels/activity of stress resistance kinases and transcription factors, and identify specific nutrient depletions capable of increasing longevity and stress resistance. Because of the conserved pro-aging role of orthologs of many of the genes in the signaling network described in this paper, these results are likely to serve as a foundation for the elucidation of similar nutrient-dependent pro-aging mechanisms in mammals.

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          Most cited references55

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          Exploring the metabolic and genetic control of gene expression on a genomic scale.

          DNA microarrays containing virtually every gene of Saccharomyces cerevisiae were used to carry out a comprehensive investigation of the temporal program of gene expression accompanying the metabolic shift from fermentation to respiration. The expression profiles observed for genes with known metabolic functions pointed to features of the metabolic reprogramming that occur during the diauxic shift, and the expression patterns of many previously uncharacterized genes provided clues to their possible functions. The same DNA microarrays were also used to identify genes whose expression was affected by deletion of the transcriptional co-repressor TUP1 or overexpression of the transcriptional activator YAP1. These results demonstrate the feasibility and utility of this approach to genomewide exploration of gene expression patterns.
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            Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.

            The present study identifies the operation of a signal tranduction pathway in mammalian cells that provides a checkpoint control, linking amino acid sufficiency to the control of peptide chain initiation. Withdrawal of amino acids from the nutrient medium of CHO-IR cells results in a rapid deactivation of p70 S6 kinase and dephosphorylation of eIF-4E BP1, which become unresponsive to all agonists. Readdition of the amino acid mixture quickly restores the phosphorylation and responsiveness of p70 and eIF-4E BP1 to insulin. Increasing the ambient amino acids to twice that usually employed increases basal p70 activity to the maximal level otherwise attained in the presence of insulin and abrogates further stimulation by insulin. Withdrawal of most individual amino acids also inhibits p70, although with differing potency. Amino acid withdrawal from CHO-IR cells does not significantly alter insulin stimulation of tyrosine phosphorylation, phosphotyrosine-associated phosphatidylinositol 3-kinase activity, c-Akt/protein kinase B activity, or mitogen-activated protein kinase activity. The selective inhibition of p70 and eIF-4E BP1 phosphorylation by amino acid withdrawal resembles the response to rapamycin, which prevents p70 reactivation by amino acids, indicating that mTOR is required for the response to amino acids. A p70 deletion mutant, p70Delta2-46/DeltaCT104, that is resistant to inhibition by rapamycin (but sensitive to wortmannin) is also resistant to inhibition by amino acid withdrawal, indicating that amino acid sufficiency and mTOR signal to p70 through a common effector, which could be mTOR itself, or an mTOR-controlled downstream element, such as a protein phosphatase.
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              The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE).

              The MSN2 and MSN4 genes encode homologous and functionally redundant Cys2His2 zinc finger proteins. A disruption of both MSN2 and MSN4 genes results in a higher sensitivity to different stresses, including carbon source starvation, heat shock and severe osmotic and oxidative stresses. We show that MSN2 and MSN4 are required for activation of several yeast genes such as CTT1, DDR2 and HSP12, whose induction is mediated through stress-response elements (STREs). Msn2p and Msn4p are important factors for the stress-induced activation of STRE dependent promoters and bind specifically to STRE-containing oligonucleotides. Our results suggest that MSN2 and MSN4 encode a DNA-binding component of the stress responsive system and it is likely that they act as positive transcription factors.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                February 2014
                6 February 2014
                : 10
                : 2
                [1 ]Dipartimento di Biotecnologie Mediche e Forensi (DiBiMeF) Università di Palermo, Palermo, Italy
                [2 ]Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Université de Lyon, Lyon, France
                [3 ]Longevity Institute and Dept. of Biological Sciences School of Gerontology, University of Southern California, Los Angeles, California, United States of America
                Stanford University Medical Center, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MGM VDL. Performed the experiments: MGM GT PF MW JH. Analyzed the data: MGM GT VDL. Contributed reagents/materials/analysis tools: PF MW JH. Wrote the paper: MGM VDL.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 13
                This study was funded, in part, by NIH/NIA grants AG20642, AG025135 and AG034906 to VDL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Gene Networks
                Model Organisms
                Molecular Cell Biology
                Signal Transduction
                Signaling in Cellular Processes
                Ras Signaling
                Tor Signaling
                Signaling Pathways
                Adenylyl Cyclase Signaling Pathway
                Mechanisms of Signal Transduction
                Cellular Stress Responses



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