proteasome endopeptidase complex


Summary: A large multisubunit complex that plays an important role in the degradation of most of the cytosolic and nuclear proteins in eukaryotic cells. It contains a 700-kDa catalytic sub-complex and two 700-kDa regulatory sub-complexes. The complex digests ubiquitinated proteins and protein activated via ornithine decarboxylase antizyme.

Top Publications

  1. ncbi Loss of autophagy in the central nervous system causes neurodegeneration in mice
    Masaaki Komatsu
    Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo ku, Tokyo 113 8613, Japan
    Nature 441:880-4. 2006
  2. ncbi The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction
    Michael H Glickman
    Faculty of Biology and the Institute for Catalysis Science and Technology, Haifa, Israel
    Physiol Rev 82:373-428. 2002
  3. ncbi FoxO3 controls autophagy in skeletal muscle in vivo
    Cristina Mammucari
    Venetian Institute of Molecular Medicine, 35129 Padova, Italy
    Cell Metab 6:458-71. 2007
  4. ncbi FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells
    Jinghui Zhao
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 6:472-83. 2007
  5. ncbi An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
    Teresa A Soucy
    Discovery, Millennium Pharmaceuticals, Inc, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA
    Nature 458:732-6. 2009
  6. pmc One step at a time: endoplasmic reticulum-associated degradation
    Shruthi S Vembar
    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    Nat Rev Mol Cell Biol 9:944-57. 2008
  7. ncbi A role for ubiquitin in selective autophagy
    Vladimir Kirkin
    Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Theodor Stern Kai 7, Frankfurt, Germany
    Mol Cell 34:259-69. 2009
  8. ncbi HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS
    Udai Bhan Pandey
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Nature 447:859-63. 2007
  9. ncbi The roles of intracellular protein-degradation pathways in neurodegeneration
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY
    Nature 443:780-6. 2006
  10. pmc Recognition and processing of ubiquitin-protein conjugates by the proteasome
    Daniel Finley
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Annu Rev Biochem 78:477-513. 2009

Detail Information

Publications302 found, 100 shown here

  1. ncbi Loss of autophagy in the central nervous system causes neurodegeneration in mice
    Masaaki Komatsu
    Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo ku, Tokyo 113 8613, Japan
    Nature 441:880-4. 2006
    ..Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies...
  2. ncbi The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction
    Michael H Glickman
    Faculty of Biology and the Institute for Catalysis Science and Technology, Haifa, Israel
    Physiol Rev 82:373-428. 2002
    ..Among these are the modes of specific and timed recognition for the degradation of the many substrates and the mechanisms that underlie aberrations in the system that lead to pathogenesis of diseases...
  3. ncbi FoxO3 controls autophagy in skeletal muscle in vivo
    Cristina Mammucari
    Venetian Institute of Molecular Medicine, 35129 Padova, Italy
    Cell Metab 6:458-71. 2007
    ..These findings point to FoxO3 and Bnip3 as potential therapeutic targets in muscle wasting disorders and other degenerative and neoplastic diseases in which autophagy is involved...
  4. ncbi FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells
    Jinghui Zhao
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 6:472-83. 2007
    ..These studies indicate that decreased IGF-1-PI3K-Akt signaling activates autophagy not only through mTOR but also more slowly by a transcription-dependent mechanism involving FoxO3...
  5. ncbi An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
    Teresa A Soucy
    Discovery, Millennium Pharmaceuticals, Inc, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA
    Nature 458:732-6. 2009
    ..MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer...
  6. pmc One step at a time: endoplasmic reticulum-associated degradation
    Shruthi S Vembar
    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    Nat Rev Mol Cell Biol 9:944-57. 2008
    ..Here, we summarize our current understanding of each step during ERAD, with emphasis on the factors that catalyse distinct activities...
  7. ncbi A role for ubiquitin in selective autophagy
    Vladimir Kirkin
    Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Theodor Stern Kai 7, Frankfurt, Germany
    Mol Cell 34:259-69. 2009
    ..This review explores the hypothesis that ubiquitin represents a selective degradation signal suitable for targeting various types of cargo, ranging from protein aggregates to membrane-bound organelles and microbes...
  8. ncbi HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS
    Udai Bhan Pandey
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Nature 447:859-63. 2007
    ..Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy...
  9. ncbi The roles of intracellular protein-degradation pathways in neurodegeneration
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY
    Nature 443:780-6. 2006
    ..However, enhancing macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of these diseases...
  10. pmc Recognition and processing of ubiquitin-protein conjugates by the proteasome
    Daniel Finley
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Annu Rev Biochem 78:477-513. 2009
    ..Here we examine the key elements of this molecular machine and how they cooperate in the processing of proteolytic substrates...
  11. ncbi RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation
    Michael H Tatham
    Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
    Nat Cell Biol 10:538-46. 2008
    ..These results demonstrate that poly-SUMO chains can act as discrete signals from mono-SUMOylation, in this case targeting a poly-SUMOylated substrate for ubiquitin-mediated proteolysis...
  12. pmc Origin and function of ubiquitin-like proteins
    Mark Hochstrasser
    Yale University, Department of Molecular Biophysics and Biochemistry, 266 Whitney Avenue, PO Box 208114, New Haven, Connecticut 06520, USA
    Nature 458:422-9. 2009
  13. ncbi Protein degradation and protection against misfolded or damaged proteins
    Alfred L Goldberg
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 426:895-9. 2003
    ..A full understanding of the pathogenesis of the protein-folding diseases will require greater knowledge of how misfolded proteins are recognized and selectively degraded...
  14. ncbi The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
    P H Maxwell
    Wellcome Trust Centre for Human Genetics, Oxford, UK
    Nature 399:271-5. 1999
    ..Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing...
  15. pmc Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization
    J A Diehl
    Howard Hughes Medical Institute, St Jude Children s Research Hospital, Memphis, Tennessee 38105 USA
    Genes Dev 12:3499-511. 1998
    ..Therefore, phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK-3beta...
  16. pmc Near-atomic resolution structural model of the yeast 26S proteasome
    Florian Beck
    Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
    Proc Natl Acad Sci U S A 109:14870-5. 2012
    ..Together with the C-terminal helices of the six PCI-domain subunits they form a very large coiled-coil bundle, which appears to serve as a flexible anchoring device for all the lid subunits...
  17. ncbi Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway
    Valérie Lallemand-Breitenbach
    Université de Paris 7 CNRS UMR 7151, Equipe Labellisée N11 Ligue Nationale Contre le Cancer, Hopital St Louis, 1, Av C Vellefaux 75475 Paris CEDEX 10 France
    Nat Cell Biol 10:547-55. 2008
    ..As PML SUMOylation recruits not only RNF4, ubiquitin and proteasomes, but also many SUMOylated proteins onto PML nuclear bodies, these domains could physically integrate the SUMOylation, ubiquitination and degradation pathways...
  18. pmc Complete subunit architecture of the proteasome regulatory particle
    Gabriel C Lander
    Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA
    Nature 482:186-91. 2012
    ..We provide a structural basis for the ability of the proteasome to degrade a diverse set of substrates and thus regulate vital cellular processes...
  19. pmc Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates
    Viktor I Korolchuk
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Mol Cell 33:517-27. 2009
    ..This will lead to increased levels of short-lived regulatory proteins, like p53, as well as the accumulation of aggregation-prone proteins, with predicted deleterious consequences...
  20. ncbi Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress
    Ulrike Seifert
    Institut für Biochemie CC2, Charite Universitatsmedizin Berlin, Oudenarder Strasse 16, D 13347 Berlin, Germany
    Cell 142:613-24. 2010
  21. pmc Misfolded proteins partition between two distinct quality control compartments
    Daniel Kaganovich
    Department of Biology and BioX Program, Stanford University, Stanford, California 94305, USA
    Nature 454:1088-95. 2008
    ..Our findings provide a framework for understanding the preferential accumulation of amyloidogenic proteins in inclusions linked to human disease...
  22. pmc A genetic interaction map of RNA-processing factors reveals links between Sem1/Dss1-containing complexes and mRNA export and splicing
    Gwendolyn M Wilmes
    Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143 2200, USA
    Mol Cell 32:735-46. 2008
    ..Finally, we show that Csn12 plays a role in pre-mRNA splicing, which is independent of other signalosome components. Thus, Sem1 is involved in three separate and functionally distinct complexes...
  23. ncbi A genomic and functional inventory of deubiquitinating enzymes
    Sebastian M B Nijman
    Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
    Cell 123:773-86. 2005
    ..In addition, we review the literature concerning these enzymes, with particular emphasis on their function, specificity, and the regulation of their activity...
  24. pmc Enhancement of proteasome activity by a small-molecule inhibitor of USP14
    Byung Hoon Lee
    Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
    Nature 467:179-84. 2010
    ..Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress...
  25. ncbi Structure and functions of the 20S and 26S proteasomes
    O Coux
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Annu Rev Biochem 65:801-47. 1996
    ..This article focuses on recent progress concerning the biochemical mechanisms and intracellular functions of the 20S and 26S proteasomes...
  26. pmc Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability
    Wen Xing Ding
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231, USA
    Am J Pathol 171:513-24. 2007
    ..Our studies thus provide a mechanistic view and elucidate the functional significance of the link between the two protein degradation systems...
  27. ncbi Selective autophagy: ubiquitin-mediated recognition and beyond
    Claudine Kraft
    Institute of Biochemistry, ETH Zurich, Schafmattstrasse 18, CH 8093 Zurich, Switzerland
    Nat Cell Biol 12:836-41. 2010
    ..On the basis of the evolutionary history of autophagic ubiquitin receptors, we propose a common origin for metazoan ubiquitin-dependent autophagy and the cytoplasm-to-vacuole targeting pathway of yeast...
  28. pmc Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells
    Esther A Obeng
    Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA
    Blood 107:4907-16. 2006
    ..These findings suggest that MM cells have a lower threshold for PI-induced UPR induction and ER stress-induced apoptosis because they constitutively express ER stress survival factors to function as secretory cells...
  29. ncbi HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin
    Atsushi Iwata
    Department of Biological Sciences, Bio X Program, Stanford University, Stanford, California 94305 5430, USA
    J Biol Chem 280:40282-92. 2005
    ..These data suggest that HDAC6-dependent retrograde transport on microtubules is used by cells to increase the efficiency and selectivity of autophagic degradation...
  30. pmc Cdc48/p97 mediates UV-dependent turnover of RNA Pol II
    Rati Verma
    California Institute of Technology, Pasadena, CA 91125, USA
    Mol Cell 41:82-92. 2011
    ..These data reveal an intimate coupling of function between proteasomes and Cdc48 that we suggest is necessary to sustain processive degradation of unstable subunits of some macromolecular protein complexes...
  31. pmc Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation
    M Lamar Seibenhener
    Program in Cell and Molecular Biosciences, Department of Biological Sciences, Auburn University, AL 36849, USA
    Mol Cell Biol 24:8055-68. 2004
    ..Altogether, our results support the hypothesis that p62 may act as a critical ubiquitin chain-targeting factor that shuttles substrates for proteasomal degradation...
  32. ncbi Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems
    Viktor I Korolchuk
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    FEBS Lett 584:1393-8. 2010
    ..Here we critically review these findings and outline some outstanding issues that still await clarification...
  33. ncbi The emerging complexity of protein ubiquitination
    David Komander
    MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK
    Biochem Soc Trans 37:937-53. 2009
    ..For example, ubiquitination may have important allosteric roles in protein regulation that are currently not appreciated...
  34. ncbi Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome
    Rati Verma
    Department of Biology and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA
    Science 298:611-5. 2002
    ..Our findings reveal an unexpected coupling between substrate deubiquitination and degradation and suggest a unifying rationale for the presence of the lid in eukaryotic proteasomes...
  35. pmc Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach
    Keren Lasker
    Department of Bioengineering and Therapeutic Sciences, California Institute of Quantitative Biosciences, 1700 4th Street, University of California, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 109:1380-7. 2012
    ..The modular structure of the 26S proteasome provides insights into the sequence of events prior to the degradation of ubiquitylated substrates...
  36. ncbi The ubiquitin-26S proteasome system at the nexus of plant biology
    Richard D Vierstra
    Department of Genetics, 425G Henry Mall, University of Wisconsin Madison, Madison, Wisconsin 53706, USA
    Nat Rev Mol Cell Biol 10:385-97. 2009
  37. ncbi Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing
    T Hoppe
    Department of Molecular Cell Biology, Max Planck Institute for Biochemistry, Martinsried, Germany
    Cell 102:577-86. 2000
    ..Intriguingly, proteasome-dependent processing of SPT23 is regulated by fatty acid pools, suggesting that the precursor itself or interacting partners are sensors of membrane composition or fluidity...
  38. ncbi Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice
    Huanjie Yang
    The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA
    Cancer Res 66:4758-65. 2006
    ..Our results show that Celastrol is a natural proteasome inhibitor that has a great potential for cancer prevention and treatment...
  39. pmc Mice completely lacking immunoproteasomes show major changes in antigen presentation
    Eleanor Z Kincaid
    Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
    Nat Immunol 13:129-35. 2012
    ..These results indicated that immunoproteasomes were more important in antigen presentation than previously thought...
  40. ncbi Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics
    Yili Yang
    Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, Maryland 21702, USA
    Cancer Res 67:9472-81. 2007
    ..These inhibitors can also be valuable tools for studying ubiquitylation...
  41. pmc The immunoproteasome, the 20S proteasome and the PA28αβ proteasome regulator are oxidative-stress-adaptive proteolytic complexes
    Andrew M Pickering
    Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089 0191, USA
    Biochem J 432:585-94. 2010
  42. ncbi The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation
    G C Meacham
    Department of Cell Biology and Cystic Fibrosis Center, University of Alabama Medical Center, 1918 University Boulevard, Birmingham, Alabama 35294 0005, USA
    Nat Cell Biol 3:100-5. 2001
    ..CHIP is a co-chaperone that converts Hsc70 from a protein-folding machine into a degradation factor that functions in endoplasmic-reticulum quality control...
  43. ncbi Global protein stability profiling in mammalian cells
    Hsueh Chi Sherry Yen
    Department of Genetics, Center for Genetics and Genomics, Brigham and Women s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Science 322:918-23. 2008
    ..The technology provides a general platform for proteome-scale analysis of protein turnover under various physiological and disease conditions...
  44. ncbi SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation
    J M Desterro
    School of Biomedical Science, University of St Andrews, Fife, United Kingdom
    Mol Cell 2:233-9. 1998
    ..Thus, while ubiquitination targets proteins for rapid degradation, SUMO-1 modification acts antagonistically to generate proteins resistant to degradation...
  45. ncbi Targeting the ubiquitin system in cancer therapy
    Daniela Hoeller
    Division of Medical Biochemistry, Innsbruck Medical University, Biocenter, Fritz Pregl Strasse 3, 6020 Innsbruck, Austria
    Nature 458:438-44. 2009
  46. pmc Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways
    Tsui Fen Chou
    Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
    Proc Natl Acad Sci U S A 108:4834-9. 2011
    ..DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy...
  47. pmc Proteasome-mediated turnover of the transcription coactivator NPR1 plays dual roles in regulating plant immunity
    Steven H Spoel
    Department of Biology, Duke University, Durham, NC 27708, USA
    Cell 137:860-72. 2009
    ..These in vivo data demonstrate dual roles for coactivator turnover in both preventing and stimulating gene transcription to regulate plant immunity...
  48. ncbi Monitoring activity and inhibition of 26S proteasomes with fluorogenic peptide substrates
    Alexei F Kisselev
    Department of Pharmacology and Toxicology, and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
    Methods Enzymol 398:364-78. 2005
    ..A novel assay of proteasome activity in crude cell extracts that allows rapid evaluation of the state of the proteasomes in cells treated with inhibitors is also described...
  49. ncbi Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome
    Reshma Shringarpure
    Ethel Percy Andrus Gerontology Center and Division of Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089 0191, USA
    J Biol Chem 278:311-8. 2003
  50. ncbi Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling
    Xiaonan Wang
    Renal Division, WMB 338, Emory University School of Medicine, M S 1930 001 1AG, 1639 Pierce Drive, Atlanta, Georgia 30322, USA
    Endocrinology 147:4160-8. 2006
    ..Thus, insulin resistance causes muscle wasting by mechanisms that involve suppression of PI3K/Akt signaling leading to activation of caspase-3 and the ubiquitin-proteasome proteolytic pathway causing muscle protein degradation...
  51. ncbi Protein degradation by the ubiquitin-proteasome pathway in normal and disease states
    Stewart H Lecker
    Nephrology Division, Beth Isreal Deaconess, Harvard Medical School, Boston, Massachusetts, USA
    J Am Soc Nephrol 17:1807-19. 2006
  52. ncbi Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway
    Jennifer S Isaacs
    Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20850, USA
    J Biol Chem 277:29936-44. 2002
  53. ncbi Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein
    Ruud Oerlemans
    Department of Rheumatology, VUMC Institute for Cancer and Immunology, VU University Medical Center, Amsterdam, The Netherlands
    Blood 112:2489-99. 2008
    ..Collectively, these findings establish a novel mechanism of bortezomib resistance associated with the selective overexpression of a mutant PSMB5 protein...
  54. ncbi Increased proteasome activity in human embryonic stem cells is regulated by PSMD11
    David Vilchez
    Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 489:304-8. 2012
    ..Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity...
  55. ncbi Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation
    Eric J Bennett
    Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA
    Mol Cell 17:351-65. 2005
    ..These data suggest a common proteotoxic mechanism for nuclear and cytoplasmic protein aggregates in the pathogenesis of neurodegenerative disease...
  56. ncbi Proteasome inhibitors in cancer therapy: lessons from the first decade
    Robert Z Orlowski
    Department of Lymphoma Myeloma, Division of Cancer Medicine, University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Clin Cancer Res 14:1649-57. 2008
    ..This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside...
  57. pmc Analysis of nucleolar protein dynamics reveals the nuclear degradation of ribosomal proteins
    Yun Wah Lam
    Division of Gene Regulation and Expression, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
    Curr Biol 17:749-60. 2007
  58. pmc The ubiquitin proteasome system in neuropathology
    Norman L Lehman
    Department of Pathology and Laboratory Medicine, Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, MI 48202, USA
    Acta Neuropathol 118:329-47. 2009
    ..The potential for the UPS as a target of pharmacological therapy is also discussed...
  59. pmc The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation
    Allan M Weissman
    Laboratory of Protein Dynamics and Signalling, National Cancer Institute, Frederick, Maryland 21702, USA
    Nat Rev Mol Cell Biol 12:605-20. 2011
    ..This observation has broad implications for pathophysiology...
  60. ncbi Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation
    P Kavsak
    Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada
    Mol Cell 6:1365-75. 2000
    ..These studies thus define Smad7 as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation...
  61. ncbi Back to the future with ubiquitin
    Cecile M Pickart
    Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
    Cell 116:181-90. 2004
    ..This perspective discusses the impact of those papers and highlights some of the subsequent insights that have led to our current appreciation of the breadth of ubiquitin-mediated signaling...
  62. ncbi Degradation of oxidized proteins by the 20S proteasome
    K J Davies
    Ethel Percy Andrus Gerontology Center, and Division of Molecular Biology, University of Southern California, Los Angeles 90089 0191, USA
    Biochimie 83:301-10. 2001
    ..Since these products of severe oxidative stress inhibit the 20S proteasome, they cause a vicious cycle of progressively worsening accumulation of cytotoxic protein oxidation products...
  63. pmc Proteasome inhibitors: an expanding army attacking a unique target
    Alexei F Kisselev
    Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
    Chem Biol 19:99-115. 2012
    ..In addition, inhibitors of ATPases and deubiquitinases of 19S regulatory particles have been discovered in the last decade...
  64. ncbi The proteasome: a suitable antineoplastic target
    Julian Adams
    Infinity Pharmaceuticals, Inc, 780 Memorial Drive, Cambridge, Massachusetts 02139, USA
    Nat Rev Cancer 4:349-60. 2004
  65. ncbi 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...
  66. ncbi Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function
    Frederic Luciano
    INSERM Unit 526, LNC Label, Faculte de Medecine, 28 Avenue de Valombrose, 06107 Nice Cedex 02, France
    Oncogene 22:6785-93. 2003
    ..Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation...
  67. pmc Mechanism of gate opening in the 20S proteasome by the proteasomal ATPases
    Julius Rabl
    Fachbereich Biologie, Chemie, Pharmazie, Freie Universitat Berlin, Takustrasse 3, 14195 Berlin, Germany
    Mol Cell 30:360-8. 2008
    ..This mechanism differs from that of PA26/28, which lacks the HbYX motif and does not cause alpha subunit rotation. These findings demonstrated how the ATPases' C termini function to facilitate substrate entry...
  68. pmc Enzymatic blockade of the ubiquitin-proteasome pathway
    Robert Ernst
    Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
    PLoS Biol 8:e1000605. 2011
    ..Our data underscore the necessity of a DUB activity for completion of the dislocation reaction and provide a new means of inhibition of proteasomal proteolysis with reduced cytotoxicity...
  69. pmc Proteasome subunit Rpn13 is a novel ubiquitin receptor
    Koraljka Husnjak
    Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Theodor Stern Kai 7, D 60590 Frankfurt Main, Germany
    Nature 453:481-8. 2008
    ..Because Rpn13 is also the proteasomal receptor for Uch37, a deubiquitinating enzyme, our findings suggest a coupling of chain recognition and disassembly at the proteasome...
  70. ncbi The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle
    Brian A Clarke
    Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA
    Cell Metab 6:376-85. 2007
    ..These data identify the mechanism by which MYH is depleted under atrophy conditions and demonstrate that inhibition of a single E3 ligase, MuRF1, is sufficient to maintain this important sarcomeric protein...
  71. pmc Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates
    Pei Hsien Ren
    Department of Biology, Stanford University, Stanford, CA 94305 5020, USA
    Nat Cell Biol 11:219-25. 2009
  72. pmc A gene expression signature shared by human mature oocytes and embryonic stem cells
    Said Assou
    CHU Montpellier, Institute for Research in Biotherapy, Hopital Saint Eloi, Montpellier, F 34000 France
    BMC Genomics 10:10. 2009
    ..Comparison of the transcriptome of these two cell types may highlight genes that are involved in pluripotency initiation...
  73. ncbi The ubiquitin-proteasome system
    Dipankar Nandi
    Department of Biochemistry, Indian Institute of Science, Bangalore
    J Biosci 31:137-55. 2006
    ..In addition, different aspects of proteasome biology are highlighted. Finally, some key roles of the UPS in different areas of biology and the use of inhibitors of this pathway as possible drug targets are discussed...
  74. ncbi Development of the proteasome inhibitor Velcade (Bortezomib)
    Julian Adams
    Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA
    Cancer Invest 22:304-11. 2004
    ..Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies...
  75. ncbi Proteolysis: from the lysosome to ubiquitin and the proteasome
    Aaron Ciechanover
    Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion Israel Institute of Technology, Efron Street, Bat Galim, Haifa 31096, Israel
    Nat Rev Mol Cell Biol 6:79-87. 2005
    ..The discovery of the ubiquitin-proteasome system resolved this enigma...
  76. ncbi The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B
    V J Palombella
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138
    Cell 78:773-85. 1994
    ..Thus, the ubiquitin-proteasome pathway functions not only in the complete degradation of polypeptides, but also in the regulated processing of precursors into active proteins...
  77. ncbi Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells
    Jian Zhong Qin
    Department of Pathology, Loyola University Medical Center, Maywood, Illinois 60153 5385, USA
    Cancer Res 65:6282-93. 2005
  78. pmc Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking
    Amy Lin
    Department of Biology, Boston University, Boston, Massachusetts, USA
    J Neurochem 119:27-39. 2011
    ..These data indicate that Nedd4 is the E3 ubiquitin ligase responsible for AMPAR ubiquitination, a modification that regulates multiple aspects of AMPAR molecular biology including trafficking, localization and stability...
  79. ncbi Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim
    Rebecca Ley
    Inositide Laboratory, Signalling Programme, The Babraham Institute, Cambridge CB2 4AT, United Kingdom
    J Biol Chem 278:18811-6. 2003
    ..Our findings provide new insights into the regulation of Bim and the role of the ERK pathway in cell survival...
  80. pmc Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability [corrected]
    King Ching Ho
    Department of Pathology and Molecular Medicine, Queen s University, Kingston, ON, Canada K7L 3N6
    Proc Natl Acad Sci U S A 108:4870-5. 2011
    ..Taking these data together, our study identifies E3 ubiquitin ligase Itch as a unique negative regulator of LATS1 and presents a possibility of targeting LATS1/Itch interaction as a therapeutic strategy in cancer...
  81. pmc VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD
    Emilie Tresse
    Department of Developmental Neurobiology, St Jude Children s Research Hospital, Memphis, TN, USA
    Autophagy 6:217-27. 2010
    ..We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes and that defect in this function may contribute to IBMPFD pathogenesis...
  82. pmc Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice
    Jie Li
    Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 East Clark Street, Lee Medical Building, Vermillion, South Dakota 57069, USA
    J Clin Invest 121:3689-700. 2011
    ..We therefore conclude that benign enhancement of cardiac proteasome proteolytic function can be achieved by CR-PA28αOE and that PFI plays a major pathogenic role in cardiac proteinopathy and myocardial I/R injury...
  83. pmc Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage
    Xing Zeng
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 18:382-95. 2010
    ..We propose that mutual antagonism between the APC and the SAC yields a positive feedback loop that amplifies the ability of TAME to induce mitotic arrest...
  84. ncbi The ubiquitylation machinery of the endoplasmic reticulum
    Christian Hirsch
    Max Delbruck Center for Molecular Medicine, Robert Rossle Strasse 10, 13125 Berlin, Germany
    Nature 458:453-60. 2009
    ..The importance of this pathway is evident from the growing list of pathologies associated with quality-control defects in the ER...
  85. ncbi Impairment of the ubiquitin-proteasome system by protein aggregation
    N F Bence
    Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA
    Science 292:1552-5. 2001
  86. ncbi Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes
    Anne Simonsen
    Department of Biochemistry, The Norwegian Radium Hospital, Montebello, Oslo 0310, Norway
    J Cell Sci 117:4239-51. 2004
    ..By electron microscopy, similar structures can be found within autophagosomes. We propose that Alfy might target cytosolic protein aggregates for autophagic degradation...
  87. ncbi Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation
    Kaisa Haglund
    Ludwig Institute for Cancer Research, Husargatan 3, SE 75 124 Uppsala, Sweden
    Nat Cell Biol 5:461-6. 2003
    ..Thus, monoubiquitination is the principal signal responsible for the movement of RTKs from the plasma membrane to the lysosome...
  88. pmc Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease
    Monte S Willis
    Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599 7126, USA
    Circ Res 106:463-78. 2010
    ..In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease...
  89. pmc Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways
    L Zhang
    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Cell Death Differ 18:864-73. 2011
    ..These results defined the critical Bcl-2 network during apoptosis and suggested that Noxa participated in triggering mitochondrial dysfunction in multiple apoptotic pathways through distinct mechanisms...
  90. pmc Ubiquitin-proteasome pathway and cellular responses to oxidative stress
    Fu Shang
    Laboratory for Nutrition and Vision Research, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
    Free Radic Biol Med 51:5-16. 2011
    ..Thus, increased levels of ubiquitin conjugates in cells seem to be an indicator of mild oxidative stress...
  91. pmc Signaling to NF-kappaB: regulation by ubiquitination
    Ingrid E Wertz
    Department of Protein Engineering, Genentech, Inc, South San Francisco, California 94080, USA
    Cold Spring Harb Perspect Biol 2:a003350. 2010
  92. pmc BAG-6 is essential for selective elimination of defective proteasomal substrates
    Ryosuke Minami
    Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan
    J Cell Biol 190:637-50. 2010
    ..Therefore, we propose that BAG-6 is necessary for ubiquitin-mediated degradation of newly synthesized defective polypeptides...
  93. pmc Inhibition of p97-dependent protein degradation by Eeyarestatin I
    Qiuyan Wang
    Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Biol Chem 283:7445-54. 2008
    ..Interestingly, p97-associated deubiquitination is also involved in degradation of a soluble substrate. Our analyses establish a role for a novel deubiquitinating process in proteasome-dependent protein turnover...
  94. ncbi Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation
    D S Campbell
    Department of Anatomy, University of Cambridge, Downing Street, CB2 3DY, Cambridge, United Kingdom
    Neuron 32:1013-26. 2001
    ..These results suggest that guidance molecules steer axon growth by triggering rapid local changes in protein levels in growth cones...
  95. ncbi Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction
    Hwan Ching Tai
    Division of Chemistry of Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
    Nat Rev Neurosci 9:826-38. 2008
    ..In this article, we discuss the molecular mechanism of protein degradation in the neuron with respect to both its function and its dysfunction...
  96. pmc Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation
    R Lin
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada
    Mol Cell Biol 18:2986-96. 1998
  97. pmc Herpes simplex virus type 1 immediate-early protein ICP0 and is isolated RING finger domain act as ubiquitin E3 ligases in vitro
    Chris Boutell
    Medical Research Council Virology Unit, Glasgow G11 5JR, Scotland, United Kingdom
    J Virol 76:841-50. 2002
    ..We conclude that ICP0 has the potential to act as an E3 ubiquitin ligase during viral infection and to target specific cellular proteins for destruction by the 26S proteasome...
  98. ncbi Endoplasmic reticulum stress compromises the ubiquitin-proteasome system
    Victoria Menendez-Benito
    Department of Cell and Molecular Biology, The Medical Nobel Institute, Karolinska Institutet, PO Box 285, Von Eulers vag 3, S 171 77 Stockholm, Sweden
    Hum Mol Genet 14:2787-99. 2005
    ..The compromised UPS during ER stress may explain the long-term gradual accumulation of misfolded proteins as well as the selective vulnerability of particular cell populations in conformational diseases...
  99. pmc Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib
    Nickolay Neznanov
    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
    Oncotarget 2:209-21. 2011
    ..These results provide support for using combination treatments that disrupt the balance of PS and HSR to increase the therapeutic index of anticancer therapies...
  100. ncbi Differential expression of genes encoding constitutive and inducible 20S proteasomal core subunits in the testis and epididymis of theophylline- or 1,3-dinitrobenzene-exposed rats
    Mark W Tengowski
    Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA
    Biol Reprod 76:149-63. 2007
    ..Complementing seminal analysis with these measures may be useful in screening drug-induced toxicity or environmental infertility...
  101. ncbi PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes
    C Gragnoli
    Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
    J Cell Physiol 212:568-71. 2007
    ..In fact, the frequency rate of such variants in unrelated cases equals 0.016. We may not exclude that PSMD9 gene variants may contribute, either commonly or rarely, to an increased risk of type 2 diabetes in other populations...

Research Grants70

  1. Pathogenesis and Treatment of Liver Disease in Transaldolase Deficiency
    Andras Perl; Fiscal Year: 2013
    ..These studies should generate fundamental new information on the cause and treatment of potentially fatal diseases of the liver. ..
  2. Mechanisms of action of ghrelin in muscle and adipose tissue in cancer-related ca
    Jose M Garcia; Fiscal Year: 2013
    ..Cachexia is also a complication of many other conditions including lung and heart disease and aging, the knowledge generated through this proposal also will help us in establishing new therapies for these conditions. ..
  3. A quantitative proteomics approach to understand viral immune evasion strategies
    Michele E Hardy; Fiscal Year: 2010
    ..Understanding these pathways and the mechanisms by which viruses evade the innate immune response may lead new approaches to attenuated vaccines or antiviral drug targets specifically designed to bypass viral evasion strategies. ..
  4. Alcohol, Proteasome Dysfunction in Liver Injury
    Craig J McClain; Fiscal Year: 2013
  5. Diverse Roles for RIC8 During G Protein Signaling in Fungi
    Katherine A Borkovich; Fiscal Year: 2012
  6. Improving Epigenetic-based Cell Reprogramming with Proteasome Inhibition
    Jaroslaw Staszkiewicz; Fiscal Year: 2011
  7. Intermediary Metabolism, Histone Acetylation, and Transcriptional Regulation
    Ales Vancura; Fiscal Year: 2013
    ..In addition, this project will provide an excellent research environment for undergraduate and graduate students, as they prepare for careers in biomedical research. ..
  8. The Role of Alcohol in HIV Therapy Hepatotoxicity
    Craig J McClain; Fiscal Year: 2012
    ..Here, we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions. ..
  9. Hepatitis B virus replication and DDB1
    Betty L Slagle; Fiscal Year: 2013
    ..This important new knowledge will reveal virus-induced changes at the post-translational level, and is predicted to provide mechanistic insight into new strategies through which to treat chronic HBV infection and prevent liver disease. ..
  10. Molecular Pathological Mechanism & Potential Therapeutics of Lafora Disease
    YAN NONE LIU; Fiscal Year: 2010
    ..Knowledge gained from this project could greatly improve the care of Lafora patients and provide very important insight for developing therapeutic agents for the treatment of the so far incurable LD patients. ..
  11. Nutrition and Anabolic Interventions in Cancer Cachexia
    Melinda Sheffield-Moore; Fiscal Year: 2013
    ..Results from this study may lead to better ways of preventing cancer-related weight loss, and improve the quality of life and survival of those affected by cervical cancer. ..
  12. Role of Vimentin in Pathogenesis of CNS Inflammation
    Sheng He Huang; Fiscal Year: 2013
    ..2). Determine how Vim and PSF contribute to IbeA-induced pathogen penetration and PMN transmigration across the BBB by SCP analysis of cBMEC and genetic blockage of Vim. ..
    ALBERT HONG JAE KIM; Fiscal Year: 2013
    ANIL KUMAR JAISWAL; Fiscal Year: 2013
    ..The studies are clinically relevant since a significant number of individuals are deficient in NQO1 and NQO2, or both due to mutations/gene alterations. ..
  15. Endothelium-Myocardium Interaction in Netrin-1 Induced Cardioprotection
    HUA LINDA CAI; Fiscal Year: 2013
    ..Characterization of the CMEC-cardiomyocyte signaling axis may additionally provide novel insights into potential cell-based therapies. ..
  16. Effect of HIV protease inhibitor on alcohol induced ER stress and liver injury.
    Cheng Ji; Fiscal Year: 2013
    ..Understanding of additive/synergistic effects of HIV PIs and alcohol on the ER stress that worsens liver injury will provide better strategies to improve care for HIV-infected patients. ..
  17. Prevalence and Impact of Frailty among Dialysis Patients
    Kirsten L Johansen; Fiscal Year: 2013
    ..abstract_text> ..
  18. mTORC1-dependent regulation of the CycC/CDK8 complex
    Jeffrey E Pessin; Fiscal Year: 2013
  19. Neprilysin and Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms
    EDWARD CHARLES DEMPSEY; Fiscal Year: 2013
  20. Treatment of stroke with a clinically approved proteasome inhibitor
    Li Zhang; Fiscal Year: 2012
    ..Therefore, in the current application, we propose to investigate the neuroprotective effects of VELCADE alone and incombination with tPA and the mechanisms underlying the beneficial effects in aged rats after embolic stroke. ..
    Maria Almira Correia; Fiscal Year: 2013
  22. Cell death regulation in proteotoxic therapy
    Wei Xing Zong; Fiscal Year: 2013
    ..At the clinical level, it may establish LC3 or SCCA1 as a molecular signature for suggesting treatment with proteotoxic agents. ..
  23. Analysis of FIP200 in signal transduction
    Jun Lin Guan; Fiscal Year: 2012
  24. Prevention of high fat diet-induced vascular injury
    Ming Hui Zou; Fiscal Year: 2013
    ..It is anticipated that the completion of this project will yield important insights into how omega-3 polyunsaturated fatty acids protect against cardiovascular diseases. ..
  25. TNF and Mitochondrial Dysfunction in ALD
    Craig J McClain; Fiscal Year: 2010
    ..abstract_text> ..
  26. Mechanisms of Ubiquitin Trafficking in Neurons
    Michael C Wooten; Fiscal Year: 2013
  27. Dysfunction of neurofilaments in disease: an iPS model of Giant Axonal Neuropathy
    ..This model will provide a platform to test for viral rescue on human MNs, which may provide the first proof of principle for the treatment of GAN using gene therapy. ..
  28. C/EBP, atrogin-1, and muscle wasting
    Per Olof Hasselgren; Fiscal Year: 2009
    ..Improved insight into mechanisms accounting for muscle wasting will help develop better treatments of this debilitating condition. ..
  29. Mechanisms of ENaC Inhibition by Replicating Influenza Virus: Role of M2 Protein
    Sadis Matalon; Fiscal Year: 2012
  30. The Role of Cks Proteins in Mammalian Meiosis
    Charles H Spruck; Fiscal Year: 2010
    ..Uncovering the function(s) of Cks2 in mammalian meiosis could lead to a better understanding about how Ml is regulated, and help to define the underlying causes of infertility and birth defects in humans. ..
  31. Identification of Inhibitors that Stabilize ER Degradation Substrates
    Domenico Tortorella; Fiscal Year: 2012
    ..These inhibitors would be effective agents against genetic disorders caused by misfolded ER proteins and pathogens that utilize the ERAD pathway. ..
    CAROL ANN LANGE; Fiscal Year: 2010
    ..This work will aid our understanding of steroid hormone action, and help to identify and implicate new therapeutic targets for breast cancer prevention and treatment. ..
  33. Heat shock protein 90 antagonist-based therapy of mantle cell lymphoma
    Kapil Bhalla; Fiscal Year: 2012
    ..This strategy involves combinations of treatments with heat shock protein 90 and proteosome inhibitors designed to target protein folding and degradation in MCL cells. ..
  34. Cytoskeletal Keratins in Epithelial Immunity to Bacterial Keratitis
    K P CONNIE TAM; Fiscal Year: 2013
    ..Results of this study will improve our understanding of how the healthy cornea resists infection and could lead to novel therapeutic strategies for controlling infections of the cornea and other sites. ..
  35. Mechanistic validation of SCF E3 ligase as a cancer and radiosensitizing target
    Yi Sun; Fiscal Year: 2013
    ..This study will validate SCF E3 ubiquitin ligase as an anticancer and radiosensitizing target and MLN4924, a newly discovered SCF E3 ligase inhibitor, as a tumor-selective and radiosensitizing agent for cancer therapy. ..
  36. 5500 Q-Trap Mass Spectrometer
    Stephen Barnes; Fiscal Year: 2010
    ..It's very well suited to obtaining quantitative data to better understand the role of the protein(s) in specific areas of public health. ..
  37. Inflammatory Cytokines Link NF-kappaB with Bim Degradation and Metastasis
    Marty W Mayo; Fiscal Year: 2012
    ..Understanding the mechanisms used by inflammatory mediators to stimulate Bim degradation will potentially result in the identification of novel approaches to preventing NSCLC metastasis. ..
  38. Inflammatory Proteases, Ubiquitin Proteasome System, and Myocyte Death
    Abdelkarim Sabri; Fiscal Year: 2012
  39. Testosterone Replacement Therapy in Advanced Chronic Kidney Disease
    Ralph Rabkin; Fiscal Year: 2009
    ..If effective in these patients, then this holds the potential of improving management of patients, not only with CKD, but also those with other muscle wasting illnesses. ..
  40. Mechanisms Involved in Age-Related Loss of Muscle Mass and Growth Response
    SUE CAROL BODINE; Fiscal Year: 2012
    ..The development of effective therapies for the enhancement of muscle recovery following atrophy in the elderly is an unmet clinical need, and is the long-term goal of the research outlined in this proposal. ..
  41. Role of p62 in Protein Aggregation and Neurodegeneration in ALS
    Haining Zhu; Fiscal Year: 2009
    ..Purchase of necessary equipment, supplies and reagents for the proposed research will also stimulate the economy as intended by the American Recovery &Reinvestment Act. ..
  42. Novel Mechanisms of Quinone Toxicity
    David Ross; Fiscal Year: 2013
    ..The studies will have broad applicability to a variety of organ systems. ..
    Mario Chojkier; Fiscal Year: 2012
    ..These studies are relevant to the hepatocyte proliferation and survival characteristic of many physiological and pathological conditions, including hepatocellular injury, liver regeneration and hepatocellular carcinoma. ..
  44. Novel Strategies for Treatment of Myeloproliferative Disorders
    Roya Khosravi-Far; Fiscal Year: 2012
    ..abstract_text> ..
  45. Rapid ischemic tolerance: Synaptic re-organization and reduced excitotoxicity
    Robert Meller; Fiscal Year: 2012
    ..It is our aim to investigate these mechanisms to help develop new therapeutics for stroke, or for circumstances where ischemia can be predicted, such as heart bypass surgery. ..
  46. Effects of Ethanol on Proteasome-HCV Core Protein Interactions
    NATALIA ALEKSANDR OSNA; Fiscal Year: 2010
    ..We envision that this research will potentially have therapeutic applications, helping to improve chronic hepatitis C treatment and vaccine development ..
  47. Modulating calcineurin signaling pathways in muscle
    Beverly A Rothermel; Fiscal Year: 2012
    ..abstract_text> ..
  48. The Pox Virion Molecular Interactome
    Paul D Gershon; Fiscal Year: 2013
  49. Targeting aberrant epigenetics by nanomedicine
    Shujun Liu; Fiscal Year: 2013
    ..abstract_text> ..
  50. Modulation of Immune senescence by induction of Ubiquitin-Proteasome systems
    Usha Ponnappan; Fiscal Year: 2012
  51. Age Effects on Liver Inflammation and Injury
    Alex B Lentsch; Fiscal Year: 2013
  52. Role of 12/15-lipoxygenase in mechanisms of muscle atrophy during aging
    Arunabh Bhattacharya; Fiscal Year: 2013
    ..abstract_text> ..
  53. Characterization of lung cancer radiosensitizers from genome-wide RNAi screens
    David Kozono; Fiscal Year: 2013
    ..In so doing, I hope to provide rationale for testing proteasome and/or USP9X inhibition in Phase I/II trials, and to identify biomarkers for patient selection. ..
  54. Neuroprotective role of RAB3B in rodent models of Parkinson's disease
    Chee Yeun Chung; Fiscal Year: 2010
    ..Our goal in this grant is to characterize the neuroprotective role of RAB3B in two different rodent models of Parkinson's disease. ..
  55. Bioavailable proteasome inhibitors as broad-spectrum antivirals
  56. Function and regulation of OATP1B1 and OATP1B3
    Wei Yue; Fiscal Year: 2013
    ..The outcomes of these experiments will greatly broaden our ability to predict and prevent transport-mediated drug-drug interactions. ..
  57. Cullin mediated protein turnover in skeletal and cardiac muscles
    Stephan Lange; Fiscal Year: 2012
    Gregory J Gores; Fiscal Year: 2013
    ..The results of these studies are germane to mechanisms of liver injury in the common syndrome of nonalcoholic fatty liver disease, and have the potential to identify new therapeutic strategies for this liver disease. ..
  59. Hepatitis C and Tumor Suppressors in Hepatocellular
    Stanley M Lemon; Fiscal Year: 2011
    ..performance site ..
  60. Biology of nuclear receptor rev-erb alpha in circadian rhythm and metabolism
    Lei Yin; Fiscal Year: 2009
    ..In addition, this work may shed the new light on identifying new therapeutic targets for treating insulin resistance and diabetes. ..
  61. Mechanisms of Gene Regulation by EBV EBNA-1 Protein
    Jeffery T Sample; Fiscal Year: 2010
  62. Experimental Therapeutics in Acute Leukemias
    William G Blum; Fiscal Year: 2010
    ..Clara Bloomfield, Dr. John Byrd, and Dr. Guido Marcucci at The Ohio State University. They will be assisted in laboratory mentoring by Dr. Denis Guttridge and Dr. James Dalton. ..
  63. High throughput screening assays to identify small molecules that target the ClpX
    Carolyn K Suzuki; Fiscal Year: 2010
    ..In addition, activators of ClpXP and/or Lon may also be exploited in the treatment of neurodegenerative disorders linked to mitochondrial protein aggregation. ..
  64. Proteasome/HDAC Inhibition in Leukemia/MDS; Phase I Trial and Correlative Studies
    Steven Grant; Fiscal Year: 2010
    Michael Freeman; Fiscal Year: 2005
    ..5) Determine if Nrf2 must be phosphorylated in order to induce ARE4. This will be approached using biochemical, genetic, and pharmacological techniques. ..
  66. A therapeutic approach to muscle wasting by limiting protein breakdown
    JEFFREY BRAULT; Fiscal Year: 2009
    ..Since these muscle atrophies share many common features, our research on therapies and mechanisms of slowing protein breakdown may lead to a viable treatment for these individuals. ..
  67. Interaction of statins with the proteasome/breast cancer
    Ekem Efuet; Fiscal Year: 2009
    ..The proposed project will contribute to the understanding of this novel action of statins, by helping to elucidate the mechanism of interaction of Lovastatin with the proteasome. ..
  68. Role of Proteasome Inhibition in the Pathogenesis of CADASIL
    Michael M Wang; Fiscal Year: 2010
    ..What is learned from this study may also provide information that will be useful for the treatment of other vascular diseases. ..
  69. Negative Regulation of Estrogen Receptors
    Carolyn Smith; Fiscal Year: 2007
    ..abstract_text> ..
  70. Chemical Genetic and Biochmechical Studies of Mitotic Proteolysis
    RANDALL KING; Fiscal Year: 2007
    ..abstract_text> ..