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Amino Acid Response

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Michael S Kilberg – One of the best experts on this subject based on the ideXlab platform.

  • regulation of the atf3 gene by a single promoter in Response to Amino Acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells
    Biochimica et Biophysica Acta, 2018
    Co-Authors: Jaclyn N Hayner, Jixiu Shan, Michael S Kilberg
    Abstract:

    Abstract Activating transcription factor 3 (ATF3) is a highly regulated protein that is implicated in a wide range of pathological conditions including inflammation and transformation. Transcription from the ATF3 gene is induced by several stress-induced signaling pathways , including Amino Acid limitation (Amino Acid Response, AAR) and ER stress (unfolded protein Response, UPR). Induction of ATF3 transcription by these pathways is mediated by ATF4 and cJUN recruitment to enhancer elements within the ATF3 gene. Although a canonical promoter (promoter A) has been studied by numerous laboratories, a second promoter activity (promoter A1), 43 kb upstream of the first, has been reported to respond to stress-induced signaling and to be critical for ATF3 expression in certain transformed cells. The results of the present study show that in normal human hepatocytes and HepG2 human hepatoma cells both basal as well as AAR- and UPR-induced transcription occurs almost exclusively from promoter A. This selectivity between the two promoters correlated with increased binding of ATF4, recruitment of RNA polymerase II , and the expected histone modifications in the promoter A region of the gene. Time course studies of ATF3 transcription activity revealed that the temporal kinetics for ATF3 induction differ between the AAR and UPR, with the former being more transient than the latter. Collectively, the results document that ATF3 expression in normal and transformed human liver originates from the canonical promoter A that responds to multiple stress signals.

  • Activation of the Amino Acid Response modulates lineage specification during differentiation of murine embryonic stem cells
    American journal of physiology. Endocrinology and metabolism, 2013
    Co-Authors: Jixiu Shan, Takashi Hamazaki, Tiffany A. Tang, Naohiro Terada, Michael S Kilberg
    Abstract:

    In somatic cells, a collection of signaling pathways activated by Amino Acid limitation have been identified and referred to as the Amino Acid Response (AAR). Despite the importance of possible detrimental effects of nutrient limitation during in vitro culture, the AAR has not been investigated in embryonic stem cells (ESC). AAR activation caused the expected increase in transcription factors that mediate specific AAR pathways, as well as the induction of asparagine synthetase, a terminal AAR target gene. Neither AAR activation nor stable knockdown of activating transcription factor (Atf) 4, a transcriptional mediator of the AAR, adversely affected ESC self-renewal or pluripotency. Low-level induction of the AAR over a 12-day period of embryoid body differentiation did alter lineage specification such that the primitive endodermal, visceral endodermal, and endodermal lineages were favored, whereas mesodermal and certain ectodermal lineages were suppressed. Knockdown of Atf4 further enhanced the AAR-induced increase in endodermal formation, suggesting that this phenomenon is mediated by an Atf4-independent mechanism. Collectively, the results indicate that, during differentiation of mouse embryoid bodies in culture, the availability of nutrients, such as Amino Acids, can influence the formation of specific cell lineages.

  • asparagine synthetase regulation by cell stress and involvement in tumor biology
    American Journal of Physiology-endocrinology and Metabolism, 2013
    Co-Authors: Mukundh N. Balasubramanian, Elizabeth A Butterworth, Michael S Kilberg
    Abstract:

    Asparagine synthetase (ASNS) catalyzes the conversion of aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. The enzyme is ubiquitous in its organ distribution in mammals, but basal expression is relatively low in tissues other than the exocrine pancreas. Human ASNS activity is highly regulated in Response to cell stress, primarily by increased transcription from a single gene located on chromosome 7. Among the genomic elements that control ASNS transcription is the C/EBP-ATF Response element (CARE) within the promoter. Protein limitation or an imbalanced dietary Amino Acid composition activate the ASNS gene through the Amino Acid Response (AAR), a process that is replicated in cell culture through limitation for any single essential Amino Acid. Endoplasmic retireticulum stress also increases ASNS transcription through the PERK-eIF2-ATF4 arm of the unfolded protein Response (UPR). Both the AAR and UPR lead to increased synthesis of ATF4, which binds to the CARE and induces ASNS transcription. Elevated expression of ASNS protein is associated with resistance to asparaginase therapy in childhood acute lymphoblastic leukemia and may be a predictive factor in drug sensitivity for certain solid tumors as well. Activation of the GCN2-eIF2-ATF4 signaling pathway, leading to increased ASNS expression appears to be a component of solid tumor adaptation to nutrient deprivation and/or hypoxia. Identifying the roles of ASNS in fetal development, tissue differentiation, and tumor growth may reveal that ASNS function extends beyond asparagine biosynthesis.

Pierre Fafournoux – One of the best experts on this subject based on the ideXlab platform.

  • Amino Acid deprivation regulates the stress-inducible gene p8 via the GCN2/ATF4 pathway
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Julien Averous, Alain Bruhat, Céline Jousse, Valérie Carraro, Yoan Cherasse, Anne-catherine Maurin, Laurent Parry, S. Lambert-langlais, Wafa B'chir, Pierre Fafournoux
    Abstract:

    In mammals, the GCN2/ATF4 pathway has been described as the main pathway involved in the regulation of gene expression upon Amino Acid limitation. This regulation is notably conferred by the presence of a cis-element called Amino Acid Response Element (AARE) in the promoter of specific genes. In vivo, the notion of Amino Acid limitation is not limited to nutritional context, indeed several pathological situations are associated with alteration of endogenous Amino Acid availability. This is notably true in the context of tumour in which the alteration of the microenvironment can lead to a perturbation in nutrient availability. P8 is a small weakly folded multifunctional protein that is overexpressed in several kinds of cancers and whose expression is induced by different stresses. In this study we have demonstrated that Amino Acid starvation was also able to induce p8 expression. Moreover, we brought the evidence, in vitro and in vivo, that the GCN2/ATF4 pathway is involved in this regulation through the presence of an AARE in p8 promoter. (C) 2011 Elsevier Inc. All rights reserved.

  • Amino Acid Availability Controls TRB3 Transcription in Liver through the GCN2/eIF2 alpha/ATF4 Pathway
    PLoS ONE, 2010
    Co-Authors: Valérie Carraro, Julien Averous, Céline Jousse, Anne-catherine Maurin, Laurent Parry, Cédric Chaveroux, Sarah Lambert-langlais, Daima Oerd, Tonis Oerd, Pierre Fafournoux
    Abstract:

    In mammals, plasma Amino Acid concentrations are markedly affected by dietary or pathological conditions. It has been well established that Amino Acids are involved in the control of gene expression. Up to now, all the information concerning the molecular mechanisms involved in the regulation of gene transcription by Amino Acid availability has been obtained in cultured cell lines. The present study aims to investigate the mechanisms involved in transcriptional activation of the TRB3 gene following Amino Acid limitation in mice liver. The results show that TRB3 is up-regulated in the liver of mice fed a leucine-deficient diet and that this induction is quickly reversible. Using transient transfection and chromatin immunoprecipitation approaches in hepatoma cells, we report the characterization of a functional Amino Acid Response Element (AARE) in the TRB3 promoter and the binding of ATF4, ATF2 and C/EBP beta to this AARE sequence. We also provide evidence that only the binding of ATF4 to the AARE plays a crucial role in the Amino Acid-regulated transcription of TRB3. In mouse liver, we demonstrate that the GCN2/eIF2 alpha/ATF4 pathway is essential for the induction of the TRB3 gene transcription in Response to a leucine-deficient diet. Therefore, this work establishes for the first time that the molecular mechanisms involved in the regulation of gene transcription by Amino Acid availability are functional in mouse liver.

  • Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals
    Molecular and cellular biology, 2009
    Co-Authors: Cédric Chaveroux, Alain Bruhat, Céline Jousse, Valérie Carraro, Yoan Cherasse, Anne-catherine Maurin, Laurent Parry, Benoit Derijard, Pierre Fafournoux
    Abstract:

    It has been well established that Amino Acid availability can control gene expression. Previous studies have shown that Amino Acid depletion induces transcription of the ATF3 (activation transcription factor 3) gene through an Amino Acid Response element (AARE) located in its promoter. This event requires phosphorylation of activating transcription factor 2 (ATF2), a constitutive AARE-bound factor. To identify the signaling cascade leading to phosphorylation of ATF2 in Response to Amino Acid starvation, we used an individual gene knockdown approach by small interfering RNA transfection. We identified the mitogen-activated protein kinase (MAPK) module MEKK1/MKK7/JNK2 as the pathway responsible for ATF2 phosphorylation on the threonine 69 (Thr69) and Thr71 residues. Then, we progressed backwards up the signal transduction pathway and showed that the GTPase Rac1/Cdc42 and the protein Gα12 control the MAPK module, ATF2 phosphorylation, and AARE-dependent transcription. Taken together, our data reveal a new signaling pathway activated by Amino Acid starvation leading to ATF2 phosphorylation and subsequently positively affecting the transcription of Amino Acid-regulated genes.

Alain Bruhat – One of the best experts on this subject based on the ideXlab platform.

  • Regulating the expression of therapeutic transgenes by controlled intake of dietary essential Amino Acids
    , 2017
    Co-Authors: Alain Bruhat, Julien Averous, Céline Jousse, Valérie Carraro, Anne-catherine Maurin, Laurent Parry, Cédric Chaveroux, Pierre Cordelier, Yuki Muranishi, A Meule
    Abstract:

    Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-ATF4 signaling pathway is specifically activated by deficiencies in any essential Amino Acid (EAA). EAA deficiency leads to rapid expression of genes regulated by AT F4-binding cis elements called Amino Acid Response Elements (AARE). We found that therapeutic genes under the control of optimized AAREs had low basal expression and high-induced expression. Briefly, after consumption of a diet deficient in one EAA, the blood concentration of the limiting EAA decreases rapidly and greatly, triggering the activation of the GCN2-ATF4 pathway and then the AARE-dependent transcription. We showed that the AARE-driven expression system can efficiently regulate the expression of a luciferase reporter gene in liver, pancreas and brain. For regulation of therapeutic transgenes over long-time periods, we performed pulses of EAA-deprived diet,swapping each of the lacking EAA. We applied our system to regulate the expression of the proapoptotic cytokine TRAIL (TNFSF10) in the context of glioma therapy and found that intermittent activation of this gene by E AA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.It exhibits the desirable properties for translation from the laboratory to clinical practice. Reference: Chaveroux et al (2016) Nature Biotechnology Jul;34(7):746-51

  • regulating the expression of therapeutic transgenes by controlled intake of dietary essential Amino Acids
    Nature Biotechnology, 2016
    Co-Authors: Cédric Chaveroux, Julien Averous, Alain Bruhat, Céline Jousse, Valérie Carraro, Anne-catherine Maurin, Laurent Parry, Florent Mesclon, Yuki Muranishi, Pierre Cordelier
    Abstract:

    Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-eIF2α signaling pathway is specifically activated by deficiencies in any essential Amino Acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized Amino Acid Response elements (AAREs) had low basal expression and high induced expression. We applied our system to regulate the expression of TNFSF10 (TRAIL) in the context of glioma therapy and found that intermittent activation of this gene by EEA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. The GCN2-eIF2α pathway is expressed in many tissues, including the brain, and is highly specific to EAA deficiency. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.

  • Amino Acid deprivation regulates the stress-inducible gene p8 via the GCN2/ATF4 pathway
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Julien Averous, Alain Bruhat, Céline Jousse, Valérie Carraro, Yoan Cherasse, Anne-catherine Maurin, Laurent Parry, S. Lambert-langlais, Wafa B'chir, Pierre Fafournoux
    Abstract:

    In mammals, the GCN2/ATF4 pathway has been described as the main pathway involved in the regulation of gene expression upon Amino Acid limitation. This regulation is notably conferred by the presence of a cis-element called Amino Acid Response Element (AARE) in the promoter of specific genes. In vivo, the notion of Amino Acid limitation is not limited to nutritional context, indeed several pathological situations are associated with alteration of endogenous Amino Acid availability. This is notably true in the context of tumour in which the alteration of the microenvironment can lead to a perturbation in nutrient availability. P8 is a small weakly folded multifunctional protein that is overexpressed in several kinds of cancers and whose expression is induced by different stresses. In this study we have demonstrated that Amino Acid starvation was also able to induce p8 expression. Moreover, we brought the evidence, in vitro and in vivo, that the GCN2/ATF4 pathway is involved in this regulation through the presence of an AARE in p8 promoter. (C) 2011 Elsevier Inc. All rights reserved.

Valérie Carraro – One of the best experts on this subject based on the ideXlab platform.

  • Regulating the expression of therapeutic transgenes by controlled intake of dietary essential Amino Acids
    , 2017
    Co-Authors: Alain Bruhat, Julien Averous, Céline Jousse, Valérie Carraro, Anne-catherine Maurin, Laurent Parry, Cédric Chaveroux, Pierre Cordelier, Yuki Muranishi, A Meule
    Abstract:

    Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-ATF4 signaling pathway is specifically activated by deficiencies in any essential Amino Acid (EAA). EAA deficiency leads to rapid expression of genes regulated by AT F4-binding cis elements called Amino Acid Response Elements (AARE). We found that therapeutic genes under the control of optimized AAREs had low basal expression and high-induced expression. Briefly, after consumption of a diet deficient in one EAA, the blood concentration of the limiting EAA decreases rapidly and greatly, triggering the activation of the GCN2-ATF4 pathway and then the AARE-dependent transcription. We showed that the AARE-driven expression system can efficiently regulate the expression of a luciferase reporter gene in liver, pancreas and brain. For regulation of therapeutic transgenes over long-time periods, we performed pulses of EAA-deprived diet,swapping each of the lacking EAA. We applied our system to regulate the expression of the proapoptotic cytokine TRAIL (TNFSF10) in the context of glioma therapy and found that intermittent activation of this gene by E AA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.It exhibits the desirable properties for translation from the laboratory to clinical practice. Reference: Chaveroux et al (2016) Nature Biotechnology Jul;34(7):746-51

  • regulating the expression of therapeutic transgenes by controlled intake of dietary essential Amino Acids
    Nature Biotechnology, 2016
    Co-Authors: Cédric Chaveroux, Julien Averous, Alain Bruhat, Céline Jousse, Valérie Carraro, Anne-catherine Maurin, Laurent Parry, Florent Mesclon, Yuki Muranishi, Pierre Cordelier
    Abstract:

    Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-eIF2α signaling pathway is specifically activated by deficiencies in any essential Amino Acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized Amino Acid Response elements (AAREs) had low basal expression and high induced expression. We applied our system to regulate the expression of TNFSF10 (TRAIL) in the context of glioma therapy and found that intermittent activation of this gene by EEA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. The GCN2-eIF2α pathway is expressed in many tissues, including the brain, and is highly specific to EAA deficiency. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.

  • Amino Acid deprivation regulates the stress-inducible gene p8 via the GCN2/ATF4 pathway
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Julien Averous, Alain Bruhat, Céline Jousse, Valérie Carraro, Yoan Cherasse, Anne-catherine Maurin, Laurent Parry, S. Lambert-langlais, Wafa B'chir, Pierre Fafournoux
    Abstract:

    In mammals, the GCN2/ATF4 pathway has been described as the main pathway involved in the regulation of gene expression upon Amino Acid limitation. This regulation is notably conferred by the presence of a cis-element called Amino Acid Response Element (AARE) in the promoter of specific genes. In vivo, the notion of Amino Acid limitation is not limited to nutritional context, indeed several pathological situations are associated with alteration of endogenous Amino Acid availability. This is notably true in the context of tumour in which the alteration of the microenvironment can lead to a perturbation in nutrient availability. P8 is a small weakly folded multifunctional protein that is overexpressed in several kinds of cancers and whose expression is induced by different stresses. In this study we have demonstrated that Amino Acid starvation was also able to induce p8 expression. Moreover, we brought the evidence, in vitro and in vivo, that the GCN2/ATF4 pathway is involved in this regulation through the presence of an AARE in p8 promoter. (C) 2011 Elsevier Inc. All rights reserved.

Céline Jousse – One of the best experts on this subject based on the ideXlab platform.

  • Regulating the expression of therapeutic transgenes by controlled intake of dietary essential Amino Acids
    , 2017
    Co-Authors: Alain Bruhat, Julien Averous, Céline Jousse, Valérie Carraro, Anne-catherine Maurin, Laurent Parry, Cédric Chaveroux, Pierre Cordelier, Yuki Muranishi, A Meule
    Abstract:

    Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-ATF4 signaling pathway is specifically activated by deficiencies in any essential Amino Acid (EAA). EAA deficiency leads to rapid expression of genes regulated by AT F4-binding cis elements called Amino Acid Response Elements (AARE). We found that therapeutic genes under the control of optimized AAREs had low basal expression and high-induced expression. Briefly, after consumption of a diet deficient in one EAA, the blood concentration of the limiting EAA decreases rapidly and greatly, triggering the activation of the GCN2-ATF4 pathway and then the AARE-dependent transcription. We showed that the AARE-driven expression system can efficiently regulate the expression of a luciferase reporter gene in liver, pancreas and brain. For regulation of therapeutic transgenes over long-time periods, we performed pulses of EAA-deprived diet,swapping each of the lacking EAA. We applied our system to regulate the expression of the proapoptotic cytokine TRAIL (TNFSF10) in the context of glioma therapy and found that intermittent activation of this gene by E AA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.It exhibits the desirable properties for translation from the laboratory to clinical practice. Reference: Chaveroux et al (2016) Nature Biotechnology Jul;34(7):746-51

  • regulating the expression of therapeutic transgenes by controlled intake of dietary essential Amino Acids
    Nature Biotechnology, 2016
    Co-Authors: Cédric Chaveroux, Julien Averous, Alain Bruhat, Céline Jousse, Valérie Carraro, Anne-catherine Maurin, Laurent Parry, Florent Mesclon, Yuki Muranishi, Pierre Cordelier
    Abstract:

    Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-eIF2α signaling pathway is specifically activated by deficiencies in any essential Amino Acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized Amino Acid Response elements (AAREs) had low basal expression and high induced expression. We applied our system to regulate the expression of TNFSF10 (TRAIL) in the context of glioma therapy and found that intermittent activation of this gene by EEA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. The GCN2-eIF2α pathway is expressed in many tissues, including the brain, and is highly specific to EAA deficiency. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.

  • Amino Acid deprivation regulates the stress-inducible gene p8 via the GCN2/ATF4 pathway
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Julien Averous, Alain Bruhat, Céline Jousse, Valérie Carraro, Yoan Cherasse, Anne-catherine Maurin, Laurent Parry, S. Lambert-langlais, Wafa B'chir, Pierre Fafournoux
    Abstract:

    In mammals, the GCN2/ATF4 pathway has been described as the main pathway involved in the regulation of gene expression upon Amino Acid limitation. This regulation is notably conferred by the presence of a cis-element called Amino Acid Response Element (AARE) in the promoter of specific genes. In vivo, the notion of Amino Acid limitation is not limited to nutritional context, indeed several pathological situations are associated with alteration of endogenous Amino Acid availability. This is notably true in the context of tumour in which the alteration of the microenvironment can lead to a perturbation in nutrient availability. P8 is a small weakly folded multifunctional protein that is overexpressed in several kinds of cancers and whose expression is induced by different stresses. In this study we have demonstrated that Amino Acid starvation was also able to induce p8 expression. Moreover, we brought the evidence, in vitro and in vivo, that the GCN2/ATF4 pathway is involved in this regulation through the presence of an AARE in p8 promoter. (C) 2011 Elsevier Inc. All rights reserved.