Randal Kaufman

Summary

Affiliation: University of Michigan
Country: USA

Publications

  1. ncbi request reprint von Willebrand factor elevates plasma factor VIII without induction of factor VIII messenger RNA in the liver
    R 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
  2. ncbi request reprint Good things come in small packages for hemophilia
    R 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
  3. pmc The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β-cells
    R J Kaufman
    Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA
    Diabetes Obes Metab 12:99-107. 2010
  4. ncbi request reprint The unfolded protein response in nutrient sensing and differentiation
    Randal 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
  5. pmc Orchestrating the unfolded protein response in health and disease
    Randal 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
  6. pmc Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism
    Randal J Kaufman
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA
    EMBO Mol Med 2:189-92. 2010
  7. ncbi request reprint Can we improve on nature? "Super molecules" of factor VIII
    R J Kaufman
    Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor 48109, USA
    Haemophilia 4:370-9. 1998
  8. ncbi request reprint Advances toward gene therapy for hemophilia at the millennium
    R 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
  9. ncbi request reprint Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls
    R 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
  10. ncbi request reprint The unfolded protein response: a stress signaling pathway critical for health and disease
    Kezhong Zhang
    Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Neurology 66:S102-9. 2006

Research Grants

  1. Unfolded Protein Response in Glucose Homeostasis
    Randal Kaufman; Fiscal Year: 2006
  2. Regulation of Factor VIII Secretion
    Randal Kaufman; Fiscal Year: 2007
  3. Role of the Unfolded Protein Response in Beta Cell
    Randal Kaufman; Fiscal Year: 2007
  4. Unfolded proteins in the Endoplasmic Reticulum to Disease
    Randal Kaufman; Fiscal Year: 2007
  5. Regulation of Factor VIII Secretion
    Randal J Kaufman; Fiscal Year: 2010
  6. Regulation of Factor VIII Secretion
    Randal Kaufman; Fiscal Year: 2005
  7. TRANSLATIONAL CONTROL IN REGULATION OF APOPTOSIS
    Randal Kaufman; Fiscal Year: 2002
  8. Conformational Diseases of the Secretory Pathway
    Randal Kaufman; Fiscal Year: 2003
  9. Regulation of ER stress-induced cell death
    Randal J Kaufman; Fiscal Year: 2010

Detail Information

Publications91

  1. ncbi request reprint von Willebrand factor elevates plasma factor VIII without induction of factor VIII messenger RNA in the liver
    R 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...
  2. ncbi request reprint Good things come in small packages for hemophilia
    R 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
  3. pmc The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β-cells
    R 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...
  4. ncbi request reprint The unfolded protein response in nutrient sensing and differentiation
    Randal 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
    ....
  5. pmc Orchestrating the unfolded protein response in health and disease
    Randal 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
  6. pmc Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism
    Randal 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...
  7. ncbi request reprint Can we improve on nature? "Super molecules" of factor VIII
    R 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...
  8. ncbi request reprint Advances toward gene therapy for hemophilia at the millennium
    R 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...
  9. ncbi request reprint Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls
    R 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
  10. ncbi request reprint The unfolded protein response: a stress signaling pathway critical for health and disease
    Kezhong 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...
  11. pmc IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response
    Kyungho 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...
  12. pmc The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis
    Kezhong 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...
  13. ncbi request reprint The unfolded protein response
    Chuan 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
  14. ncbi request reprint Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha
    Chuan 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...
  15. ncbi request reprint Cytoplasmic IRE1alpha-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress
    Sung 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...
  16. ncbi request reprint Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis
    Donalyn 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...
  17. pmc The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response
    Jiahai 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...
  18. ncbi request reprint Signaling the unfolded protein response from the endoplasmic reticulum
    Kezhong 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
  19. pmc Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells
    Sung 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...
  20. ncbi request reprint trans-Autophosphorylation by the isolated kinase domain is not sufficient for dimerization or activation of the dsRNA-activated protein kinase PKR
    Shiyong 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...
  21. pmc The unfolded protein response represses differentiation through the RPD3-SIN3 histone deacetylase
    Martin 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...
  22. ncbi request reprint IRE1- and HAC1-independent transcriptional regulation in the unfolded protein response of yeast
    Martin 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...
  23. ncbi request reprint ER stress signaling by regulated splicing: IRE1/HAC1/XBP1
    Sung 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...
  24. pmc The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes
    Donalyn 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...
  25. ncbi request reprint Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis
    Shiyong 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...
  26. ncbi request reprint Ultraviolet light inhibits translation through activation of the unfolded protein response kinase PERK in the lumen of the endoplasmic reticulum
    Shiyong 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...
  27. pmc UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators
    D 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...
  28. ncbi request reprint All roads lead to ATF4
    D 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...
  29. ncbi request reprint The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain
    Chuan 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...
  30. ncbi request reprint Regulation of mRNA translation by protein folding in the endoplasmic reticulum
    Randal 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...
  31. pmc Regulation of apoptosis by the unfolded protein response
    Andrew 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...
  32. pmc Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum
    Kenjiro 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...
  33. ncbi request reprint A trip to the ER: coping with stress
    D 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...
  34. ncbi request reprint That which does not kill me makes me stronger: adapting to chronic ER stress
    D 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...
  35. ncbi request reprint The noncatalytic portion of human UDP-glucose: glycoprotein glucosyltransferase I confers UDP-glucose binding and transferase function to the catalytic domain
    Stacey 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...
  36. ncbi request reprint Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure
    Edward 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...
  37. ncbi request reprint The unfolded protein response is required for haploid tolerance in yeast
    Kyungho 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...
  38. ncbi request reprint ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress
    Jun 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...
  39. ncbi request reprint Double-stranded RNA-dependent protein kinase phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 mediates apoptosis
    Donalyn 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...
  40. ncbi request reprint Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa
    Andrew 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
    ....
  41. ncbi request reprint 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
    ....
  42. pmc Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans
    Xiaohua 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...
  43. pmc Optimization of protease-inhibitor interactions by randomizing adventitious contacts
    Tomoko 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
    ....
  44. ncbi request reprint The unfolded protein response--a stress signaling pathway of the endoplasmic reticulum
    Xiaohua 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...
  45. pmc Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins
    D 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...
  46. ncbi request reprint The double-stranded RNA-activated protein kinase mediates viral-induced encephalitis
    Donalyn 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...
  47. pmc The endoplasmic reticulum and the unfolded protein response
    Jyoti 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...
  48. pmc The role of p58IPK in protecting the stressed endoplasmic reticulum
    D 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...
  49. pmc From endoplasmic-reticulum stress to the inflammatory response
    Kezhong 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...
  50. pmc Regulation of ER stress-induced macroautophagy by protein kinase C
    Kenjiro 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...
  51. pmc Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2
    Bin Zhang
    Life Sciences Institute, Department of Internal Medicine, 210 Washtenaw Ave, Ann Arbor, MI 48109 0650, USA
    Blood 107:1903-7. 2006
    ....
  52. ncbi request reprint LMAN1 and MCFD2 form a cargo receptor complex and interact with coagulation factor VIII in the early secretory pathway
    Bin 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...
  53. ncbi request reprint Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex
    Bin 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...
  54. ncbi request reprint Bioengineering of coagulation factor VIII for improved secretion
    Hongzhi 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...
  55. pmc Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes
    Benbo 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...
  56. ncbi request reprint Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response
    Kezhong 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...
  57. pmc Identification and characterization of endoplasmic reticulum stress-induced apoptosis in vivo
    Kezhong Zhang
    Department of Biological Chemistry, The University of Michigan Medical Center, Ann Arbor, Michigan, USA
    Methods Enzymol 442:395-419. 2008
    ....
  58. pmc Antioxidants reduce endoplasmic reticulum stress and improve protein secretion
    Jyoti 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...
  59. ncbi request reprint Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway
    Christophe 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...
  60. pmc Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux
    Jie 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...
  61. ncbi request reprint IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo
    Benjamin 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...
  62. pmc Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses
    Hao 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...
  63. pmc Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway
    Zsolt 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...
  64. ncbi request reprint Activation of GCN2 in UV-irradiated cells inhibits translation
    Jing 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...
  65. ncbi request reprint The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader
    Ibrahim 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...
  66. ncbi request reprint TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the cevelopment of atherosclerosis in hyperhomocysteinemia
    Gazi 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...
  67. pmc MEK signaling is required for phosphorylation of eIF2alpha following amino acid limitation of HepG2 human hepatoma cells
    Michelle 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...
  68. ncbi request reprint A time-dependent phase shift in the mammalian unfolded protein response
    Hiderou Yoshida
    Graduate School of Biostudies, Kyoto University, Kyoto 606 8304, Japan
    Dev Cell 4:265-71. 2003
    ....
  69. ncbi request reprint Compromised calnexin function in calreticulin-deficient cells
    Rai 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...
  70. pmc Genotype-phenotype correlation in combined deficiency of factor V and factor VIII
    Bin 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...
  71. ncbi request reprint Regulation of ERGIC-53 gene transcription in response to endoplasmic reticulum stress
    Maurizio 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...
  72. pmc Inhibition of the ubiquitin-proteasome system induces stress granule formation
    Rachid 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...
  73. ncbi request reprint The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4
    Li 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...
  74. pmc Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression
    Heather 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...
  75. pmc Nck-dependent activation of extracellular signal-regulated kinase-1 and regulation of cell survival during endoplasmic reticulum stress
    Duc 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...
  76. pmc ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
    Meixia 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...
  77. ncbi request reprint Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II
    Keisuke 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...
  78. pmc Stress granules and processing bodies are dynamically linked sites of mRNP remodeling
    Nancy 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...
  79. pmc Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2
    Jing 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...
  80. ncbi request reprint A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress
    Michael 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...
  81. pmc Reovirus induces and benefits from an integrated cellular stress response
    Jennifer A Smith
    Department of Microbiology, University of Minnesota, 420 Delaware Street SE, MMC 196, Minneapolis, MN 55455, USA
    J Virol 80:2019-33. 2006
    ....
  82. pmc Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation
    Yukako 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...
  83. pmc Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival
    Sara 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...
  84. ncbi request reprint Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells
    Dirk 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...
  85. pmc Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2
    Phoebe D Lu
    Skirball Institute, New York University School of Medicine, New York, NY, USA
    EMBO J 23:169-79. 2004
    ....
  86. pmc Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2alpha phosphorylation
    Rachid 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...
  87. ncbi request reprint Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response
    Keith 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...
  88. pmc 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 expression
    Ping 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...
  89. ncbi request reprint Divergent roles of IRE1alpha and PERK in the unfolded protein response
    Martin Schroder
    School of Biological and Biomedical Sciences, University of Durham, UK
    Curr Mol Med 6:5-36. 2006
    ....
  90. pmc Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control
    Marianne 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...
  91. ncbi request reprint Ribosome stalling regulates IRES-mediated translation in eukaryotes, a parallel to prokaryotic attenuation
    James 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 Grants27

  1. Unfolded Protein Response in Glucose Homeostasis
    Randal 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. ..
  2. Regulation of Factor VIII Secretion
    Randal Kaufman; Fiscal Year: 2007
    ..The information will be vital to the future development of improved gene therapy protocols for hemophilia A ..
  3. Role of the Unfolded Protein Response in Beta Cell
    Randal 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. ..
  4. Unfolded proteins in the Endoplasmic Reticulum to Disease
    Randal Kaufman; Fiscal Year: 2007
    ....
  5. Regulation of Factor VIII Secretion
    Randal J Kaufman; Fiscal Year: 2010
    ..The information will be vital to the future development of improved gene therapy protocols for hemophilia A. ..
  6. Regulation of Factor VIII Secretion
    Randal 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. ..
  7. TRANSLATIONAL CONTROL IN REGULATION OF APOPTOSIS
    Randal Kaufman; Fiscal Year: 2002
    ....
  8. Conformational Diseases of the Secretory Pathway
    Randal 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. ..
  9. Regulation of ER stress-induced cell death
    Randal 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. ..