Research Topics
Species | Randal KaufmanSummaryAffiliation: University of Michigan Country: USA Publications
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Publications
von Willebrand factor elevates plasma factor VIII without induction of factor VIII messenger RNA in the liverR J Kaufman
Howard Hughes Medical Institute and the Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
Blood 93:193-7. 1999..These results indicate that the secondary rise in factor VIII levels in response to exogenous vWF infusion is not dependent on increased steady-state levels of factor VIII mRNA in the liver...- Good things come in small packages for hemophiliaR J Kaufman
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-0650, USA
J Thromb Haemost 1:2472-3. 2003 - The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in ?-cellsR J Kaufman
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA
Diabetes Obes Metab 12:99-107. 2010..The findings suggest an unprecedented link by which protein synthesis and/or misfolding in the ER causes oxidative stress and should encourage the development of novel strategies to treat diabetes... - The unfolded protein response in nutrient sensing and differentiationRandal J Kaufman
Department of Biological Chemistry, University of Michigan Medical Center, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109 0650, USA
Nat Rev Mol Cell Biol 3:411-21. 2002.... - Orchestrating the unfolded protein response in health and diseaseRandal J Kaufman
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor 48109-0650, USA
J Clin Invest 110:1389-98. 2002 - Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolismRandal J Kaufman
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA
EMBO Mol Med 2:189-92. 2010..A series of recent studies reveal novel and potentially ancient roles for this pathway in the coordination of metabolic and immune responses... - Can we improve on nature? "Super molecules" of factor VIIIR J Kaufman
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor 48109, USA
Haemophilia 4:370-9. 1998..In addition, there are now structural models of factor VIII available that should in the future direct development of novel peptidomimetics that may eventually overcome the requirement for replacement therapy with factor VIII protein... - Advances toward gene therapy for hemophilia at the millenniumR J Kaufman
Department of Biological Chemistry and Howard Hughes Medical Institute, The University of Michigan Medical Center, Ann Arbor 48109 0650, USA
Hum Gene Ther 10:2091-107. 1999..In addition, several gene therapy clinical studies for the treatment of hemophilia A and B were initiated in 1999... - Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controlsR J Kaufman
Department of Biological Chemistry and Howard Hughes Medical Institute, The University of Michigan Medical Center, Ann Arbor, Michigan 48109-0650 USA
Genes Dev 13:1211-33. 1999 - The unfolded protein response: a stress signaling pathway critical for health and diseaseKezhong Zhang
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Neurology 66:S102-9. 2006..This review summarizes the complex regulation of UPR signaling and its relevance to human physiology and disease... - IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein responseKyungho Lee
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
Genes Dev 16:452-66. 2002..Both processing of ATF6 and IRE1alpha-mediated splicing of XBP1 mRNA are required for full activation of the UPR... - The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesisKezhong Zhang
Department of Biological Chemistry and Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
J Clin Invest 115:268-81. 2005..These results suggest specific requirements of the IRE1alpha-mediated UPR subpathway in the early and late stages of B lymphopoiesis... - The unfolded protein responseChuan Yin Liu
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0650, USA
J Cell Sci 116:1861-2. 2003 - Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alphaChuan Yin Liu
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109 0650, USA
J Biol Chem 278:17680-7. 2003..e. covalent interactions involving disulfide bond formation and hydrophobic interactions, with the hydrophobic interaction being the driving force for dimerization... - Cytoplasmic IRE1alpha-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stressSung Hoon Back
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109 0650, USA
J Biol Chem 281:18691-706. 2006..We propose that XBP1 mRNA cytoplasmic splicing provides a novel mechanism to rapidly induce translation of a transcription factor in response to a specific stimulus... - Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasisDonalyn Scheuner
Howard Hughes Medical Institute, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, Michigan 48109, USA
Nat Med 11:757-64. 2005..We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes... - The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein responseJiahai Zhou
Life Sciences Institute, LSI 3163B, Department of Biological Chemistry, University of Michigan Medical Center, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA
Proc Natl Acad Sci U S A 103:14343-8. 2006..Our structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling... - Signaling the unfolded protein response from the endoplasmic reticulumKezhong Zhang
Department of Biological Chemistry and Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
J Biol Chem 279:25935-8. 2004 - Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cellsSung Hoon Back
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109 0650, USA
Cell Metab 10:13-26. 2009..The finding that increased proinsulin synthesis causes oxidative damage in beta cells may reflect events in the beta cell failure associated with insulin resistance in type 2 diabetes... - trans-Autophosphorylation by the isolated kinase domain is not sufficient for dimerization or activation of the dsRNA-activated protein kinase PKRShiyong Wu
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
Biochemistry 43:11027-34. 2004..The results imply that even though the isolated kinase domain of PKR phosphorylates intact PKR and eIF2alpha, it is unable to activate PKR... - The unfolded protein response represses differentiation through the RPD3-SIN3 histone deacetylaseMartin Schroder
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA
EMBO J 23:2281-92. 2004..These data also define for the first time a gene class that is under negative control by the UPR, and provide the framework for a novel mechanism through which bZIP proteins repress transcription... - IRE1- and HAC1-independent transcriptional regulation in the unfolded protein response of yeastMartin Schroder
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA
Mol Microbiol 49:591-606. 2003..Core promoter activation was observed upon diverse cellular stresses, suggesting it represents a primordial stress-induced gene activation mechanism... - ER stress signaling by regulated splicing: IRE1/HAC1/XBP1Sung Hoon Back
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-0650, USA
Methods 35:395-416. 2005..Especially we think the newly developed quantitative and qualitative methods to detect IRE1 activity-dependent XBP1 mRNA splicing will be fast and accurate tools to show the activation of the UPR... - The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetesDonalyn Scheuner
Department of Biological Chemistry, and Howard Hughes Medical Institute, The University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
Endocr Rev 29:317-33. 2008..Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve beta-cell function and/or survival in the treatment of diabetes... - Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesisShiyong Wu
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
J Biol Chem 279:34898-902. 2004..Based upon our results, we propose a novel mechanism by which UV light regulates early phase NFkappaB activation by means of an ER-stress-induced translational inhibition pathway... - Ultraviolet light inhibits translation through activation of the unfolded protein response kinase PERK in the lumen of the endoplasmic reticulumShiyong Wu
Department of Radiation Oncology and Biological Chemistry, The Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
J Biol Chem 277:18077-83. 2002..These results support a novel mechanism by which UV irradiation regulates translation via an endoplasmic reticulum-stress signaling pathway... - UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulatorsD Thomas Rutkowski
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Dev Cell 15:829-40. 2008..These results reveal an unanticipated direct link between ER homeostasis and the transcriptional regulation of metabolism, and suggest mechanisms by which ER stress might underlie fatty liver disease... - All roads lead to ATF4D Thomas Rutkowski
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Dev Cell 4:442-4. 2003..Exploring the consequences of this event has highlighted the ways in which stress is sensed and responded to via many distinct pathways... - The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domainChuan Yin Liu
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109 0650, USA
J Biol Chem 277:18346-56. 2002..Interestingly, we demonstrated that the NLD forms stable dimers linked by intermolecular disulfide bridges. Our data support that the luminal domain represents a novel ligand-independent dimerization domain... - Regulation of mRNA translation by protein folding in the endoplasmic reticulumRandal J Kaufman
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, 1150 W Medical Center Drive, Ann Arbor, MI 48109 0650, USA
Trends Biochem Sci 29:152-8. 2004..This review summarizes recent insights into the mechanisms that couple protein translation with protein folding in the ER... - Regulation of apoptosis by the unfolded protein responseAndrew Fribley
Department of Biological Chemistry, The University of Michigan Medical Center, Ann Arbor, MI, USA
Methods Mol Biol 559:191-204. 2009..In this chapter, we summarize our current understanding of UPR-induced apoptosis and various methods to detect ER stress and apoptosis in mammalian cells... - Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulumKenjiro Sakaki
Department of Biological Chemistry, University of Michigan Medical School, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA
J Biol Chem 283:15370-80. 2008..These observations indicate that Ca(2+)-dependent PKC activation is specifically required for autophagy in response to ER stress but not in response to amino acid starvation... - A trip to the ER: coping with stressD Thomas Rutkowski
Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109-0650, USA
Trends Cell Biol 14:20-8. 2004..This review highlights advances in these areas and attempts to forecast important issues that must be addressed soon... - That which does not kill me makes me stronger: adapting to chronic ER stressD Thomas Rutkowski
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Trends Biochem Sci 32:469-76. 2007..Recent advances have improved our understanding of ER stress and the vertebrate UPR, which suggest possible mechanisms by which cells adapt to chronic stress... - The noncatalytic portion of human UDP-glucose: glycoprotein glucosyltransferase I confers UDP-glucose binding and transferase function to the catalytic domainStacey M Arnold
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109 0650, USA
J Biol Chem 278:43320-8. 2003..The results indicate that the amino-terminal 80% of HUGT1 is required for activation of the catalytic domain, whereas the homologous portion of HUGT2 cannot provide this function... - Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposureEdward McEwen
Howard Hughes Medical Institute and the Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor 48109, USA
J Biol Chem 280:16925-33. 2005..The results demonstrated an essential role for HRI in mediating arsenite stress-induced phosphorylation of eukaryotic translation initiation factor 2alpha, inhibition of protein synthesis, stress granule formation, and survival... - The unfolded protein response is required for haploid tolerance in yeastKyungho Lee
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
J Biol Chem 278:11818-27. 2003..Inhibition of the UPR pathway induces autodiploidization, and constitutive activation of UPR target genes suppresses this response... - ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stressJun Wu
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Dev Cell 13:351-64. 2007..These results suggest that the vertebrate ATF6alpha pathway evolved to maintain ER function when cells are challenged with chronic stress and provide a rationale for the overlap among the three UPR pathways... - Double-stranded RNA-dependent protein kinase phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 mediates apoptosisDonalyn Scheuner
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, 48109 0650, USA
J Biol Chem 281:21458-68. 2006..We propose that eIF2alpha phosphorylation is fundamentally a death signal, yet it may promote either death or survival, depending upon coincident signaling events... - Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of NoxaAndrew M Fribley
Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI 48109 1078, USA
J Biol Chem 281:31440-7. 2006.... - Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?Jyoti D Malhotra
Howard Hughes Medical Institute and Departments of Biological Chemistry and Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
Antioxid Redox Signal 9:2277-93. 2007.... - Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegansXiaohua Shen
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, USA
PLoS Genet 1:e37. 2005..Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution... - Optimization of protease-inhibitor interactions by randomizing adventitious contactsTomoko Komiyama
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Proc Natl Acad Sci U S A 100:8205-10. 2003.... - The unfolded protein response--a stress signaling pathway of the endoplasmic reticulumXiaohua Shen
Howard Hughes Medical Institute, The University of Michigan Medical Center, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA
J Chem Neuroanat 28:79-92. 2004..This review summarizes our understanding of the UPR signaling developed in the recent years... - Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteinsD Thomas Rutkowski
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan, USA
PLoS Biol 4:e374. 2006..It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome... - The double-stranded RNA-activated protein kinase mediates viral-induced encephalitisDonalyn Scheuner
Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA
Virology 317:263-74. 2003..They support PKR to be an effective target to control tissue damage due to deleterious host responses to viral infection... - The endoplasmic reticulum and the unfolded protein responseJyoti D Malhotra
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, United States
Semin Cell Dev Biol 18:716-31. 2007..Persistent protein misfolding initiates apoptotic cascades that are now known to play fundamental roles in the pathogenesis of multiple human diseases including diabetes, atherosclerosis and neurodegenerative diseases... - The role of p58IPK in protecting the stressed endoplasmic reticulumD Thomas Rutkowski
Howard Hughes Medical Institute and Departments of Biological Chemistry and Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109 0650, USA
Mol Biol Cell 18:3681-91. 2007..These results identify a previously unanticipated location for p58(IPK) in the ER lumen where its putative function as a cochaperone explains the stress-sensitivity phenotype of knockout cells and mice... - From endoplasmic-reticulum stress to the inflammatory responseKezhong Zhang
Department of Biological Chemistry, The University of Michigan Medical Center, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA
Nature 454:455-62. 2008..The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation... - Regulation of ER stress-induced macroautophagy by protein kinase CKenjiro Sakaki
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109 0650, USA
Autophagy 4:841-3. 2008..Herein, we review and discuss the significance of these findings with respect to regulation of autophagy in response to ER stress... - Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2Bin Zhang
Life Sciences Institute, Department of Internal Medicine, 210 Washtenaw Ave, Ann Arbor, MI 48109-0650, USA
Blood 107:1903-7. 2006.... - LMAN1 and MCFD2 form a cargo receptor complex and interact with coagulation factor VIII in the early secretory pathwayBin Zhang
Life Sciences Institute, the Departments of Biological Chemistry, Internal Medicine, Human Genetics Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, USA
J Biol Chem 280:25881-6. 2005..MCFD2 may function to specifically recruit factor V and factor VIII to sites of transport vesicle budding within the endoplasmic reticulum lumen... - Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complexBin Zhang
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109 0650, USA
Nat Genet 34:220-5. 2003..MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1. These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins... - Bioengineering of coagulation factor VIII for improved secretionHongzhi Z Miao
Department of Pediatrics, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Blood 103:3412-9. 2004..FVIII bioengineered for improved secretion will significantly increase potential for success in gene therapy strategies for hemophilia A as well as improve recombinant FVIII production in cell culture manufacturing or transgenic animals... - Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetesBenbo Song
Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA
J Clin Invest 118:3378-89. 2008..These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in beta cells under conditions of increased insulin demand... - Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory responseKezhong Zhang
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Cell 124:587-99. 2006..Together, our studies delineate a molecular mechanism for activation of an ER-localized transcription factor, CREBH, and reveal an unprecedented link by which ER stress initiates an acute inflammatory response... - Identification and characterization of endoplasmic reticulum stress-induced apoptosis in vivoKezhong Zhang
Department of Biological Chemistry, The University of Michigan Medical Center, Ann Arbor, Michigan, USA
Methods Enzymol 442:395-419. 2008.... - Antioxidants reduce endoplasmic reticulum stress and improve protein secretionJyoti D Malhotra
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Proc Natl Acad Sci U S A 105:18525-30. 2008..Genetic or chemical intervention to reduce reactive oxygen species improves protein folding and cell survival and may provide an avenue to treat and/or prevent diseases of protein misfolding... - Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathwayChristophe Denoyelle
Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500E Medical Center Drive, 4217 CCGC, Ann Arbor, MI 48109, USA
Nat Cell Biol 8:1053-63. 2006..These results argue against premature senescence as a converging mechanism of response to activating oncogenes and support a direct role of the ER as a gatekeeper of tumour control... - Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide fluxJie Shang
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
J Cell Biol 176:605-16. 2007..Thus, by sensing ER stress from defective glycosylation, PERK can restore ER homeostasis by balancing polypeptide synthesis with flux through the LLO pathway... - IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivoBenjamin Drogat
INSERM E0113, Universite Bordeaux I, Bâtiment B2, Avenue des Facultes, Falence F 33400, France
Cancer Res 67:6700-7. 2007..Our results therefore suggest an essential role for IRE1-dependent signaling pathways in response to ischemia and identify this protein as a potential therapeutic target to control both the angiogenic switch and tumor development... - Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stressesHao Yuan Jiang
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
Mol Cell Biol 23:5651-63. 2003..The absence of NF-kappaB-mediated transcription and its antiapoptotic function provides an explanation for why eIF2alpha kinase deficiency in diseases such as Wolcott-Rallison syndrome leads to cellular apoptosis and disease... - Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathwayZsolt Talloczy
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
Proc Natl Acad Sci U S A 99:190-5. 2002..5. Thus, autophagy is a novel evolutionarily conserved function of the eIF2alpha kinase pathway that is targeted by viral virulence gene products... - Activation of GCN2 in UV-irradiated cells inhibits translationJing Deng
Department of Biochemistry and McGill Cancer Centre, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Quebec, Canada
Curr Biol 12:1279-86. 2002..While the effects of UV irradiation on DNA replication and transcription have been extensively studied, the mechanism(s) responsible for translational repression are poorly understood... - The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leaderIbrahim Yaman
Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Cell 113:519-31. 2003..This study suggests that the structure of the IRES is dynamic and regulation of this RNA structure is a mechanism of translational control... - TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the cevelopment of atherosclerosis in hyperhomocysteinemiaGazi S Hossain
Department of Pathology and Molecular Medicine, McMaster University and the Henderson Research Centre, Hamilton, Ontario L8V 1C3, Canada
J Biol Chem 278:30317-27. 2003..Collectively, these findings provide evidence that TDAG51 is induced by homocysteine, promotes detachment-mediated PCD, and contributes to the development of atherosclerosis observed in hyperhomocysteinemia... - MEK signaling is required for phosphorylation of eIF2alpha following amino acid limitation of HepG2 human hepatoma cellsMichelle M Thiaville
Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, Florida 32610, USA
J Biol Chem 283:10848-57. 2008..Collectively, these results document a critical interdependence between the MEK-ERK MAPK signaling pathway and the amino acid stress-activated pathway... - A time-dependent phase shift in the mammalian unfolded protein responseHiderou Yoshida
Graduate School of Biostudies, Kyoto University, Kyoto 606 8304, Japan
Dev Cell 4:265-71. 2003.... - Compromised calnexin function in calreticulin-deficient cellsRai Knee
Department of Biochemistry, Canadian Institutes of Health Research Membrane Protein Research Group, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
Biochem Biophys Res Commun 304:661-6. 2003..We show that the absence of calreticulin can have devastating effects on the function of the others, compromising overall quality control of the secretory pathway and activating UPR-dependent pathways... - Genotype-phenotype correlation in combined deficiency of factor V and factor VIIIBin Zhang
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA
Blood 111:5592-600. 2008..These data suggest that MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2... - Regulation of ERGIC-53 gene transcription in response to endoplasmic reticulum stressMaurizio Renna
Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Salerno, Fisciano Salerno I 84034, Italy
J Biol Chem 282:22499-512. 2007..A molecular model for the transcriptional regulation of the ERGIC-53 gene is proposed... - Inhibition of the ubiquitin-proteasome system induces stress granule formationRachid Mazroui
McGill University, Department of Biochemistry, Montreal, Quebec, Canada
Mol Biol Cell 18:2603-18. 2007..Hence, our findings suggest that SGs could be considered as one of the players that mediate the early response of the cell to proteasome inhibitors by interfering temporarily with mRNA decay pathways... - The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4Li Chung Hsu
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0636, USA
Nature 428:341-5. 2004..The pro-apoptotic actions of PKR are mediated both through inhibition of protein synthesis and activation of interferon response factor 3... - Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expressionHeather P Harding
Skirball Institute of Biomolecular Medicine, New York University, New York, New York 10016, USA
Cell Metab 2:361-71. 2005..These findings suggest a mechanism by which interactions between sterol metabolism, the ISR, and the SREBP pathway affect lipid metabolism during ER stress... - Nck-dependent activation of extracellular signal-regulated kinase-1 and regulation of cell survival during endoplasmic reticulum stressDuc Thang Nguyen
Department of Surgery, McGill University, Montreal, Quebec, H3A 1A1 Canada
Mol Biol Cell 15:4248-60. 2004..These data delineate a novel mechanism for the regulation of ER stress signaling to the MAPK pathway and demonstrate a critical role for Nck in ER stress and cell survival... - ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growthMeixia Bi
Department of Radiation Oncology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
EMBO J 24:3470-81. 2005..Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities... - Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-IIKeisuke Yamamoto
Graduate School of Biostudies, Kyoto University, Kyoto 606 8502, Japan
J Biochem 136:343-50. 2004..Accordingly, the induction of Herp mRNA was diminished in the absence of XBP1 whereas that of BiP mRNA was not affected. These results may help in understanding the role of Herp in the quality control system in the ER... - Stress granules and processing bodies are dynamically linked sites of mRNP remodelingNancy Kedersha
Division of Rheumatology and Immunology, Harvard Medical School, Brigham and Women s Hospital, Boston, MA 02115, USA
J Cell Biol 169:871-84. 2005..We propose that mRNA released from disassembled polysomes is sorted and remodeled at SGs, from which selected transcripts are delivered to PBs for degradation... - Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2Jing Deng
New York University Medical Center, SI 3 10, 540 First Ave, New York, NY 10016, USA
Mol Cell Biol 24:10161-8. 2004..These studies suggest a direct role for eIF2alpha phosphorylation-dependent translational control in activating NF-kappaB during ER stress... - A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stressMichael Boyce
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Science 307:935-9. 2005..More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events... - Reovirus induces and benefits from an integrated cellular stress responseJennifer A Smith
Department of Microbiology, University of Minnesota, 420 Delaware Street SE, MMC 196, Minneapolis, MN 55455, USA
J Virol 80:2019-33. 2006.... - Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradationYukako Oda
Department of Molecular and Cellular Biology Institute for Frontier Medical Sciences, Graduate School of Science, Kyoto University, Sakyo ku, Kyoto 606 8502, Japan
J Cell Biol 172:383-93. 2006..These findings indicate that Derlin-2 and -3 provide the missing link between EDEM and p97 in the process of degrading misfolded glycoproteins... - Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survivalSara B Cullinan
The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA
Mol Cell Biol 23:7198-209. 2003..Our data demonstrate that Nrf2 is a critical effector of PERK-mediated cell survival... - Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cellsDirk Vander Mierde
Gene Expression Unit, Department of Molecular Cell Biology, KU Leuven, Herestraat 49, B 3000 Leuven, Belgium
Endocrinology 148:609-17. 2007..Because defects in the pancreatic endoplasmic reticulum kinase-eIF2alpha signaling system lead to beta-cell failure and diabetes, deregulation of the PP1 system could likewise lead to cellular dysfunction and disease... - Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2Phoebe D Lu
Skirball Institute, New York University School of Medicine, New York, NY, USA
EMBO J 23:169-79. 2004.... - Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2alpha phosphorylationRachid Mazroui
Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6
Mol Biol Cell 17:4212-9. 2006..We propose that SG modeling can occur via both eIF2alpha phosphorylation-dependent and -independent pathways that target translation initiation... - Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein responseKeith D Tardif
Department of Microbiology and Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
J Biol Chem 279:17158-64. 2004..Therefore, HCV may suppress the IRE1-XBP1 pathway to not only promote HCV expression but also to contribute to the persistence of the virus in infected hepatocytes... - Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expressionPing Hu
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 702 Light Hall, Nashville, TN 37232 0615, USA
Mol Cell Biol 26:3071-84. 2006..Thus, ER stress induces two signals, namely TNF-alpha induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor... - Divergent roles of IRE1alpha and PERK in the unfolded protein responseMartin Schroder
School of Biological and Biomedical Sciences, University of Durham, UK
Curr Mol Med 6:5-36. 2006.... - Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational controlMarianne Koritzinsky
Department of Radiation Oncology (MAASTRO, GROW Research Institute, University of Maastricht, The Netherlands
EMBO J 25:1114-25. 2006..Together, our data indicate that acute and prolonged hypoxia regulates mRNA translation through distinct mechanisms, each with important contributions to hypoxic gene expression... - Ribosome stalling regulates IRES-mediated translation in eukaryotes, a parallel to prokaryotic attenuationJames Fernandez
Departments of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Mol Cell 17:405-16. 2005..This control is reminiscent of translation attenuation in prokaryotic operons, where inhibition of translation elongation can regulate both mRNA translation and gene transcription by altering mRNA structure...
Research Grants
- Unfolded Protein Response in Glucose HomeostasisRandal Kaufman; Fiscal Year: 2006..These in vivo models have the potential for providing novel biologic insights into human disease and may also facilitate testing of new therapies. ..
- Regulation of Factor VIII SecretionRandal Kaufman; Fiscal Year: 2007..The information will be vital to the future development of improved gene therapy protocols for hemophilia A ..
- Role of the Unfolded Protein Response in Beta CellRandal Kaufman; Fiscal Year: 2007..Excessive insulin synthesis can lead to accumulation of unfolded protein within the ¿ cell. The study of cell signaling pathways activated by unfolded protein will lead to insights and new treatments for this disease. ..
- Unfolded proteins in the Endoplasmic Reticulum to DiseaseRandal Kaufman; Fiscal Year: 2007....
- Regulation of Factor VIII SecretionRandal J Kaufman; Fiscal Year: 2010..The information will be vital to the future development of improved gene therapy protocols for hemophilia A. ..
- Regulation of Factor VIII SecretionRandal Kaufman; Fiscal Year: 2005..Elucidating the mechanisms of protein folding, retention, and transport through the ER will have impact on the ability to therapeutically intervene in disease states that are associated with defective protein folding in the ER. ..
- TRANSLATIONAL CONTROL IN REGULATION OF APOPTOSISRandal Kaufman; Fiscal Year: 2002....
- Conformational Diseases of the Secretory PathwayRandal Kaufman; Fiscal Year: 2003..This conference will focus on new technologies and methodologies to study this rapidly moving field in order to dissect the complexity and diversity of ER function. ..
- Regulation of ER stress-induced cell deathRandal J Kaufman; Fiscal Year: 2010..The proposed studies on protein synthesis will provide vital information that should encourage the development of novel therapeutics to treat diabetes. ..