Regulation of Gene Expression During Stress

Summary

Principal Investigator: Maria Hatzoglou
Abstract: DESCRIPTION (provided by applicant): The role of amino acid status as a signaling event and the pathway by which it signals resulting in [unreadable] cell apoptosis has not been evaluated as a causative event. Beyond the consequences of hyperglycemia and hyperlipidemia, additional molecular mechanism (s) that cause [unreadable] cell apoptosis during development of diabetes are not well studied but will be vital for the development of novel diagnostic and therapeutic strategies. Apoptosis of [unreadable] cells in Type 2 Diabetes (T2DM) is associated with increased stress in the endoplasmic reticulum (ER). Our laboratory has contributed a body of work on the cellular responses to diverse stress conditions, including ER stress and amino acid limitation. Combined work from many labs has shown that the cellular response to ER stress involves the translation and transcriptional reprogramming of cells. We discovered a novel anabolic program that accompanies the translational recovery of late ER stress. This program promotes amino acid uptake, increased tRNA charging, and increased expression of genes involved in protein synthesis. This program which has prosurvival and growth actions under mild stress, paradoxically, promote apoptosis under conditions of chronic stress, by stimulating protein synthesis, by inducing the production of reactive oxygen species, and by exhausting the ATP supply. We propose to study the molecular mechanism of this novel 'suicide'adaptive stress response in insulinoma cells and islets from diabetic mouse models. We will study (i) the mechanisms of transcriptional and translational control, (ii) the mechanism and significance of increased amino acid uptake in the regulation of mRNA translation and (iii) the mechanism via which increased methionine and cystine uptake contribute to protection of [unreadable] cells from ER stress-induced apoptosis. Our studies will reveal novel biomarkers in ER stress-induced diabetes (a condition related to T2DM), with diagnostic and therapeutic potential.
Funding Period: 1998-01-01 - 2018-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Amino acid starvation induces the SNAT2 neutral amino acid transporter by a mechanism that involves eukaryotic initiation factor 2alpha phosphorylation and cap-independent translation
    Francesca Gaccioli
    Departments of Nutrition and Biochemistry, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA
    J Biol Chem 281:17929-40. 2006
  2. pmc Function of phosphoenolpyruvate carboxykinase in mammary gland epithelial cells
    Chang Wen Hsieh
    Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA
    J Lipid Res 52:1352-62. 2011
  3. pmc Characterization of hibernating ribosomes in mammalian cells
    Dawid Krokowski
    Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
    Cell Cycle 10:2691-702. 2011
  4. pmc Requirement of rRNA methylation for 80S ribosome assembly on a cohort of cellular internal ribosome entry sites
    Abhijit Basu
    Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
    Mol Cell Biol 31:4482-99. 2011
  5. pmc Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway
    Zineb Mounir
    Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec H3T1E2, Canada
    Sci Signal 4:ra62. 2011
  6. pmc A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation
    Mithu Majumder
    Departments of Nutrition, Case Western University School of Medicine, Cleveland, Ohio, USA
    Mol Cell Biol 32:992-1003. 2012
  7. pmc Transcriptional repression of ATF4 gene by CCAAT/enhancer-binding protein β (C/EBPβ) differentially regulates integrated stress response
    Souvik Dey
    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 287:21936-49. 2012
  8. pmc Genome-wide identification and quantitative analysis of cleaved tRNA fragments induced by cellular stress
    Mridusmita Saikia
    Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Biol Chem 287:42708-25. 2012
  9. pmc ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
    Jaeseok Han
    Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
    Nat Cell Biol 15:481-90. 2013
  10. pmc A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux
    Dawid Krokowski
    Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Biol Chem 288:17202-13. 2013

Research Grants

  1. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
  2. Role of the Unfolded Protein Response in Beta Cell
    Randal J Kaufman; Fiscal Year: 2013
  3. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
  4. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
  5. MECHANISMS OF BETA CELL FAILURE
    Domenico Accili; Fiscal Year: 2013
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
  7. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
  8. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
  9. Genetic and Metabolic Fingerprints of Coativators "Program Project"
    BERT W O'MALLEY; Fiscal Year: 2013
  10. System Biology Center in New York
    SRINIVAS RAVI V IYENGAR; Fiscal Year: 2013

Detail Information

Publications25

  1. ncbi Amino acid starvation induces the SNAT2 neutral amino acid transporter by a mechanism that involves eukaryotic initiation factor 2alpha phosphorylation and cap-independent translation
    Francesca Gaccioli
    Departments of Nutrition and Biochemistry, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA
    J Biol Chem 281:17929-40. 2006
    ..In contrast, the response to hypertonic stress does not involve eukaryotic initiation factor 2alpha phosphorylation, suggesting that SNAT2 expression can be modulated by specific signaling pathways in response to different stresses...
  2. pmc Function of phosphoenolpyruvate carboxykinase in mammary gland epithelial cells
    Chang Wen Hsieh
    Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA
    J Lipid Res 52:1352-62. 2011
    ..Therefore, Pck1 plays an important role in both the mammary gland adipocytes and epithelial cells during lactation...
  3. pmc Characterization of hibernating ribosomes in mammalian cells
    Dawid Krokowski
    Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
    Cell Cycle 10:2691-702. 2011
    ..The identification of ribosomal dimers in rat cells will bring new insights in our thinking of the ribosome structure and its function during the cellular response to stress conditions...
  4. pmc Requirement of rRNA methylation for 80S ribosome assembly on a cohort of cellular internal ribosome entry sites
    Abhijit Basu
    Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
    Mol Cell Biol 31:4482-99. 2011
    ..This work reveals a novel mechanism operating on a cohort of cellular IRESs that involves rRNA methylation for proper 80S complex assembly and efficient translation initiation...
  5. pmc Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway
    Zineb Mounir
    Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec H3T1E2, Canada
    Sci Signal 4:ra62. 2011
    ..Thus, we suggest that the PERK-eIF2αP pathway provides a link between Akt signaling and translational control, which has implications for tumor formation and treatment...
  6. pmc A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation
    Mithu Majumder
    Departments of Nutrition, Case Western University School of Medicine, Cleveland, Ohio, USA
    Mol Cell Biol 32:992-1003. 2012
    ..We propose a model in which eIF2α phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress response transcription program and the ER's capacity for protein folding during stress...
  7. pmc Transcriptional repression of ATF4 gene by CCAAT/enhancer-binding protein β (C/EBPβ) differentially regulates integrated stress response
    Souvik Dey
    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 287:21936-49. 2012
    ....
  8. pmc Genome-wide identification and quantitative analysis of cleaved tRNA fragments induced by cellular stress
    Mridusmita Saikia
    Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Biol Chem 287:42708-25. 2012
    ..Identification of the stress-specific tRNA cleavage mechanisms and patterns will provide insights into the role of tRNA fragments in signaling pathways and stress-related disorders...
  9. pmc ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
    Jaeseok Han
    Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
    Nat Cell Biol 15:481-90. 2013
    ..The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER...
  10. pmc A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux
    Dawid Krokowski
    Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Biol Chem 288:17202-13. 2013
    ..These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes...
  11. pmc Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor eIF2α
    Bo Jhih Guan
    From the Department of Pharmacology
    J Biol Chem 289:12593-611. 2014
    ..These studies advance our knowledge on the complexity of the communicating signaling pathways in controlling protein synthesis rates during chronic stress. ..
  12. pmc Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states
    Anton A Komar
    Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA
    Cell Cycle 10:229-40. 2011
    ....
  13. pmc Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency
    Hala Muaddi
    Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, QC, H3T 1E2, Canada
    Mol Biol Cell 21:3220-31. 2010
    ..Our data demonstrate that eIF2α phosphorylation is a significant determinant of survival and adaptation of glucose-deficient cells with possible important implications in biological processes that interfere with glucose metabolism...
  14. pmc Molecular symbiosis of CHOP and C/EBP beta isoform LIP contributes to endoplasmic reticulum stress-induced apoptosis
    Calin Bogdan Chiribau
    Department of Nutrition, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 4954, USA
    Mol Cell Biol 30:3722-31. 2010
    ..In view of the positive effect of CHOP-LIP interaction in mediating their proapoptotic functions, we propose this functional cooperativity as molecular symbiosis between proteins...
  15. pmc A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation
    Alex B Lopez
    Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106 4906, USA
    Biochem J 402:163-73. 2007
    ..These results suggest that the transient increase in cat-1 transcription is due to transcriptional activation caused by ATF4 followed by transcriptional repression by ATF3 via a feedback mechanism...
  16. pmc An efficient in vitro translation system from mammalian cells lacking the translational inhibition caused by eIF2 phosphorylation
    Vladimir V Zeenko
    Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA
    RNA 14:593-602. 2008
    ..In addition, cell-free systems from differentiated cells with the Ser51Ala mutation should provide a means for investigating cell type-specific features of protein synthesis...
  17. pmc Preserved protein synthesis in the heart in response to acute fasting and chronic food restriction despite reductions in liver and skeletal muscle
    Celvie L Yuan
    Department of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA
    Am J Physiol Endocrinol Metab 295:E216-22. 2008
    ..We conclude that cardiac protein synthesis is maintained in cases of nutritional perturbations, in strong contrast to liver and gastrocnemius muscle, where protein synthesis is decreased by acute fasting or chronic food restriction...
  18. pmc Differential control of the CCAAT/enhancer-binding protein beta (C/EBPbeta) products liver-enriched transcriptional activating protein (LAP) and liver-enriched transcriptional inhibitory protein (LIP) and the regulation of gene expression during the respo
    Yi Li
    Department of Nutrition, School of Medicine, Case Western University, Cleveland, Ohio 44106 4954, USA
    J Biol Chem 283:22443-56. 2008
    ..We conclude that regulation of LIP/LAP ratios during ER stress is a novel mechanism for modulating the cellular stress response...
  19. pmc A stress-responsive RNA switch regulates VEGFA expression
    Partho Sarothi Ray
    Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
    Nature 457:915-9. 2009
    ....
  20. pmc The hnRNA-binding proteins hnRNP L and PTB are required for efficient translation of the Cat-1 arginine/lysine transporter mRNA during amino acid starvation
    Mithu Majumder
    Department of Nutrition, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 4954, USA
    Mol Cell Biol 29:2899-912. 2009
    ..It is proposed that PTB and hnRNP L are positive regulators of Cat-1 mRNA translation via the IRES under stress conditions that cause a global decrease of protein synthesis...
  21. pmc The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells
    Saverio Tardito
    Unit of General and Clinical Pathology, Department of Experimental Medicine, University of Parma, Parma, Italy
    J Biol Chem 284:24306-19. 2009
    ..A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2alpha phosphorylation and the UPR...
  22. pmc A bifunctional intronic element regulates the expression of the arginine/lysine transporter Cat-1 via mechanisms involving the purine-rich element binding protein A (Pur alpha)
    Charlie C Huang
    Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 4954, USA
    J Biol Chem 284:32312-20. 2009
    ..In addition, we propose that genes may use stress-response elements such as the INE to support basal expression in the absence of stress...
  23. pmc eIF2alpha phosphorylation tips the balance to apoptosis during osmotic stress
    Elena Bevilacqua
    Department of Nutrition, Case Western University School of Medicine, Cleveland, Ohio 44106, USA
    J Biol Chem 285:17098-111. 2010
    ..We propose that eIF2alpha phosphorylation during hypertonic stress promotes apoptosis by sequestration of specific mRNAs in SGs in a process mediated by the cytoplasmic accumulation of hnRNP A1...
  24. pmc Temporal regulation of Cat-1 (cationic amino acid transporter-1) gene transcription during endoplasmic reticulum stress
    Charlie C Huang
    Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 044106, USA
    Biochem J 429:215-24. 2010
    ..We propose that the signalling via phosphorylated eIF2alpha is required for maximum induction of Cat-1 transcription during the UPR by inducing the accumulation of both ATF4 and XBP1s...
  25. ncbi Expression of glutamine transporter Slc38a3 (SNAT3) during acidosis is mediated by a different mechanism than tissue-specific expression
    Sarojini Balkrishna
    Research School of Biology, Australian National University, Canberra, ACT, Australia
    Cell Physiol Biochem 33:1591-606. 2014
    ..Transcription of the glutamine transporter SNAT3 (Slc38a3) for instance is highly up-regulated in the kidney during metabolic acidosis to provide glutamine for ammonia production...

Research Grants30

  1. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  2. Role of the Unfolded Protein Response in Beta Cell
    Randal J Kaufman; Fiscal Year: 2013
    ..Is Atfda and/or Atfdp deletion detrimental to p cells upon I r e l d ''deletion, HFD feeding, or Akita mutation? ..
  3. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  4. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  5. MECHANISMS OF BETA CELL FAILURE
    Domenico Accili; Fiscal Year: 2013
    ..The PI proposes to use a combination of developmental and epigenetic analyse coupled with candidate gene approaches to understand the mechanism by which FoxO control ?-cell maturation. ..
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  7. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  8. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  9. Genetic and Metabolic Fingerprints of Coativators "Program Project"
    BERT W O'MALLEY; Fiscal Year: 2013
    ..When complete, this PPG will afford a much greater understanding of NR and coregulator biology and will help define novel therapeutic leverage points for intervention of diseases associated with MS. ..
  10. System Biology Center in New York
    SRINIVAS RAVI V IYENGAR; Fiscal Year: 2013
    ..abstract_text> ..
  11. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  12. Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA)
    Christopher J Evans; Fiscal Year: 2013
    ..Balleine, Bonci, Koob, Levitt, Nestler and Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a Pilot Program for the center. ..
  13. REGULATION OF LIVER GROWTH AND FUNCTION
    Leonard S Jefferson; Fiscal Year: 2013
    ..Knowledge gained from the project will provide insight into designing strategies for treatment of pathologies resulting from the maladapted whole body metabolism associated with obesity and diabetes. ..
  14. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  15. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  16. Translational Control by Osmotically Active Solutes
    Maria Hatzoglou; Fiscal Year: 2013
    ..These studies will increase our understanding of stress-induced human diseases and generate biological markers that can be used for drug development. ..
  17. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  18. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  19. The effect of bariatric surgery on carbohydrate metabolism
    Adrian Vella; Fiscal Year: 2013
    ..Understanding the effect of these interventions on glucose metabolism and GLP-1 secretion (amongst other gut hormones) will immeasurably increase our ability to develop new treatment strategies in individuals affected with diabetes. ..
  20. Age-Induced Impairment of Nutrient Signaling Results in Bone Loss
    CARLOS MIGUEL ISALES; Fiscal Year: 2013
    ..Ultimately, we expect the Program Project to identify new therapeutic strategies and develop specific countermeasures for age-associated declines in musculoskeletal function. ..
  21. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  22. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  23. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..