ubiquitin protein ligases

Summary

Summary: A diverse class of enzymes that interact with UBIQUITIN-CONJUGATING ENZYMES and ubiquitination-specific protein substrates. Each member of this enzyme group has its own distinct specificity for a substrate and ubiquitin-conjugating enzyme. Ubiquitin-protein ligases exist as both monomeric proteins multiprotein complexes.

Top Publications

  1. ncbi Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
    T Kitada
    Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    Nature 392:605-8. 1998
  2. ncbi Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
    H Shimura
    Department of Neurology, Juntendo University School of Medicine, Bunkyo ku, Tokyo, Japan
    Nat Genet 25:302-5. 2000
  3. ncbi Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex
    Ning Zheng
    Cellular Biochemistry and Biophysics Program, Memorial Sloan Kettering Cancer Center, New York 10021, USA
    Nature 416:703-9. 2002
  4. ncbi The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
    M Scheffner
    Laboratory of Tumor Virus Biology, National Cancer Institute, Bethesda, Maryland 20892
    Cell 75:495-505. 1993
  5. ncbi Function and regulation of cullin-RING ubiquitin ligases
    Matthew D Petroski
    Division of Biology and Howard Hughes Medical Institute, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA
    Nat Rev Mol Cell Biol 6:9-20. 2005
  6. pmc Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants
    Jessica C Greene
    Department of Genome Sciences, University of Washington, P O Box 357730, Seattle, WA 98195, USA
    Proc Natl Acad Sci U S A 100:4078-83. 2003
  7. ncbi Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis
    Qing Zhong
    Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 75390, USA
    Cell 121:1085-95. 2005
  8. ncbi Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain
    L Deng
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas 75390, USA
    Cell 103:351-61. 2000
  9. pmc Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7
    Masayoshi Yada
    Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi ku, Fukuoka, Fukuoka, Japan
    EMBO J 23:2116-25. 2004
  10. ncbi Themes and variations on ubiquitylation
    A M Weissman
    Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 1152, USA
    Nat Rev Mol Cell Biol 2:169-78. 2001

Detail Information

Publications428 found, 100 shown here

  1. ncbi Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
    T Kitada
    Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    Nature 392:605-8. 1998
    ..Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product 'Parkin'...
  2. ncbi Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
    H Shimura
    Department of Neurology, Juntendo University School of Medicine, Bunkyo ku, Tokyo, Japan
    Nat Genet 25:302-5. 2000
    ....
  3. ncbi Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex
    Ning Zheng
    Cellular Biochemistry and Biophysics Program, Memorial Sloan Kettering Cancer Center, New York 10021, USA
    Nature 416:703-9. 2002
    ..The structure suggests that Cul1 may contribute to catalysis through the positioning of the substrate and the ubiquitin-conjugating enzyme, and this model is supported by Cul1 mutations designed to eliminate the rigidity of the scaffold...
  4. ncbi The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
    M Scheffner
    Laboratory of Tumor Virus Biology, National Cancer Institute, Bethesda, Maryland 20892
    Cell 75:495-505. 1993
    ..The ubiquitination of p53 requires the E1 enzyme and a novel E2 in mammalian cells, while E3 activity is conferred by the E6-E6-AP complex. Furthermore, E6-AP appears to have ubiquitin-protein ligase activity in the absence of E6...
  5. ncbi Function and regulation of cullin-RING ubiquitin ligases
    Matthew D Petroski
    Division of Biology and Howard Hughes Medical Institute, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA
    Nat Rev Mol Cell Biol 6:9-20. 2005
    ..In this review, we focus on the composition, regulation and function of cullin-RING ligases, and describe how these enzymes can be characterized by a set of general principles...
  6. pmc Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants
    Jessica C Greene
    Department of Genome Sciences, University of Washington, P O Box 357730, Seattle, WA 98195, USA
    Proc Natl Acad Sci U S A 100:4078-83. 2003
    ....
  7. ncbi Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis
    Qing Zhong
    Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 75390, USA
    Cell 121:1085-95. 2005
    ..Thus, Mule is a unique BH3-containing E3 ubiquitin ligase apical to Bcl-2 family proteins during DNA damage-induced apoptosis...
  8. ncbi Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain
    L Deng
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas 75390, USA
    Cell 103:351-61. 2000
    ..These results unveil a new regulatory function for ubiquitin, in which IKK is activated through the assembly of K63-linked polyubiquitin chains...
  9. pmc Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7
    Masayoshi Yada
    Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi ku, Fukuoka, Fukuoka, Japan
    EMBO J 23:2116-25. 2004
    ..Accumulation of c-Myc was also apparent in mouse Fbw7-/- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively...
  10. ncbi Themes and variations on ubiquitylation
    A M Weissman
    Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 1152, USA
    Nat Rev Mol Cell Biol 2:169-78. 2001
    ..A few years ago, we could only have dreamt of the complex arsenal of enzymes dedicated to ubiquitylation. Why has nature come up with so many ways of doing what seems to be such a simple job?..
  11. ncbi Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases
    N Zheng
    Cellular Biochemistry and Biophysics Program, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Cell 102:533-9. 2000
    ....
  12. pmc The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation
    Markus Welcker
    Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Proc Natl Acad Sci U S A 101:9085-90. 2004
    ..Because Fbw7 mediates the degradation of cyclin E, Notch, and c-Jun, as well as c-Myc, the loss of Fbw7 is likely to elicit profound effects on cell proliferation during tumorigenesis...
  13. ncbi Association between early-onset Parkinson's disease and mutations in the parkin gene
    C B Lücking
    INSERM Unité 289, Hopital de la Salpetriere, Paris
    N Engl J Med 342:1560-7. 2000
    ..Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients...
  14. ncbi Physiological functions of the HECT family of ubiquitin ligases
    Daniela Rotin
    Program in Cell Biology, The Hospital for Sick Children, Ontario, Canada
    Nat Rev Mol Cell Biol 10:398-409. 2009
    ..The physiological functions of the yeast HECT E3 ligase Rsp5 are the best known, but the functions of HECT E3 enyzmes in metazoans are now becoming clearer from in vivo studies...
  15. ncbi UBE3A/E6-AP mutations cause Angelman syndrome
    T Kishino
    Genetics Division, Children s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Genet 15:70-3. 1997
    ..Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease...
  16. ncbi Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin
    Nicole Exner
    Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
    J Neurosci 27:12413-8. 2007
    ..Our results may therefore suggest that PINK1 deficiency in humans results in mitochondrial abnormalities associated with cellular stress, a pathological phenotype, which can be ameliorated by enhanced expression of parkin...
  17. ncbi Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade
    L Huang
    Cellular Biochemistry and Biophysics Program, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Science 286:1321-6. 1999
    ..The crystal structure of the E6AP hect domain bound to the UbcH7 ubiquitin-conjugating enzyme (E2) reveals the determinants of E2-E3 specificity and provides insights into the transfer of ubiquitin from the E2 to the E3...
  18. 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...
  19. pmc OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD
    John C Christianson
    Department of Biological Sciences and Bio X Program, Stanford University, Lorry Lokey Bldg, 337 Campus Drive, Stanford, CA 94305, USA
    Nat Cell Biol 10:272-82. 2008
    ..These data suggest that XTP3-B and OS-9 are components of distinct, partially redundant, quality control surveillance pathways that coordinate protein folding with membrane dislocation and ubiquitin conjugation in mammalian cells...
  20. ncbi Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1
    G Levkowitz
    Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Mol Cell 4:1029-40. 1999
    ..Our study identifies Cbl proteins as components of the ubiquitin ligation machinery and implies that they similarly suppress many other signaling pathways...
  21. pmc The E3 ubiquitin ligase Itch controls the protein stability of p63
    Mario Rossi
    Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom
    Proc Natl Acad Sci U S A 103:12753-8. 2006
    ..These data suggest that Itch has a fundamental role in the mechanism that controls endogenous p63 protein levels and therefore contributes to regulation of p63 in physiological conditions...
  22. ncbi Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta
    Motoyuki Itoh
    Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD 20892, USA
    Dev Cell 4:67-82. 2003
    ..This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells...
  23. ncbi Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase
    D M Koepp
    Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA
    Science 294:173-7. 2001
    ..Multiple F-box proteins contribute to cyclin E stability in yeast, suggesting an overlap in SCF E3 ligase specificity that allows combinatorial control of cyclin E degradation...
  24. pmc Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1
    Y Zhang
    Departments of Neurology, Neuroscience, and Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287 0005, USA
    Proc Natl Acad Sci U S A 97:13354-9. 2000
    ..The loss of Parkin's ubiquitin-protein ligase function in familial-linked mutations suggests that this may be the cause of familial autosomal recessive Parkinson's disease...
  25. 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...
  26. pmc The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
    Benjamin J Thompson
    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
    J Exp Med 204:1825-35. 2007
    ..Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL...
  27. ncbi Mitochondrial dysfunction and oxidative damage in parkin-deficient mice
    James J Palacino
    Center for Neurologic Diseases, Brigham and Women s Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 279:18614-22. 2004
    ....
  28. 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...
  29. ncbi The ubiquitin ligase COP1 is a critical negative regulator of p53
    David Dornan
    Department of Molecular Oncology, Genentech, Inc, 1 DNA Way, South San Francisco, California 94080, USA
    Nature 429:86-92. 2004
    ..Overall, these results indicate that COP1 is a critical negative regulator of p53 and represents a new pathway for maintaining p53 at low levels in unstressed cells...
  30. pmc Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling
    Wei Li
    Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA
    PLoS ONE 3:e1487. 2008
    ..These findings suggest the existence of a new, Ub-mediated mechanism responsible for integration of mitochondria into the cellular environment...
  31. ncbi Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease
    H Shimura
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Science 293:263-9. 2001
    ..These findings demonstrate a critical biochemical reaction between the two PD-linked gene products and suggest that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional PD...
  32. 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...
  33. ncbi Mechanisms underlying ubiquitination
    C M Pickart
    School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, Maryland 21205, USA
    Annu Rev Biochem 70:503-33. 2001
    ..The new findings shed light on many aspects of E3 structure, function, and mechanism, but also emphasize that key features of E3 catalysis remain to be elucidated...
  34. ncbi Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53
    S Fang
    Laboratory of Immune Cell Biology, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892 1152, USA
    J Biol Chem 275:8945-51. 2000
    ..However, this RING was ineffective in ubiquitination and proteasomal targeting of p53, suggesting that there may be specificity at the level of the RING in the recognition of heterologous substrates...
  35. ncbi Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases
    Bing Hao
    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Mol Cell 26:131-43. 2007
    ....
  36. pmc FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors
    Jennifer O'Neil
    Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    J Exp Med 204:1813-24. 2007
    ....
  37. pmc Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1
    Jarrod W Heck
    Section of Cell and Developmental Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 107:1106-11. 2010
    ..The broad conservation of Ubr ligases and the relevant chaperones indicates that these mechanisms will be important in understanding both basic and biomedical aspects of cellular proteostasis...
  38. ncbi Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover
    Christy J Fryer
    Regulatory Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Mol Cell 16:509-20. 2004
    ..These findings suggest a role for MAM and CycC:CDK8 in the turnover of the Notch enhancer complex at target genes...
  39. ncbi The nucleoporin RanBP2 has SUMO1 E3 ligase activity
    Andrea Pichler
    Max Planck Institute for Biochemistry, Am Klopferspitz 18a, 82152 Martinsried, Germany
    Cell 108:109-20. 2002
    ..Our findings place SUMOylation at the cytoplasmic filaments of the NPC and suggest that, at least for some substrates, modification and nuclear import are linked events...
  40. ncbi CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity
    Yuzuru Imai
    Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute, Saitama 351 0198, Japan
    Mol Cell 10:55-67. 2002
    ..Furthermore, CHIP enhanced the ability of Parkin to inhibit cell death induced by Pael-R. Taken together, these results indicate that CHIP is a mammalian E4-like molecule that positively regulates Parkin E3 activity...
  41. ncbi Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis
    H Zou
    Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
    Science 285:418-22. 1999
    ..The oncogenic nature of increased expression of vSecurin may result from chromosome gain or loss, produced by errors in chromatid separation...
  42. ncbi Disjunction of homologous chromosomes in meiosis I depends on proteolytic cleavage of the meiotic cohesin Rec8 by separin
    S B Buonomo
    Research Institute of Molecular Pathology, University of Vienna, Austria
    Cell 103:387-98. 2000
    ..We show here that cleavage of Rec8 by separin at one of two different sites is necessary for the resolution of chiasmata and the disjunction of homologous chromosomes during meiosis...
  43. ncbi SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box
    C Bai
    Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA
    Cell 86:263-74. 1996
    ..Different skp1 mutants arrest cells in either G1 or G2, suggesting a connection between regulation of proteolysis in different stages of the cycle...
  44. pmc Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson's disease
    Steven A Beasley
    Department of Biochemistry, University of Western Ontario, London, ON, Canada N6A 5C1
    Proc Natl Acad Sci U S A 104:3095-100. 2007
    ....
  45. ncbi Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase
    Bao Liang Song
    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Mol Cell 19:829-40. 2005
    ..The current results identify gp78 as the E3 that initiates sterol-accelerated degradation of reductase, and Insig-1 as a bridge between gp78/VCP and the reductase substrate...
  46. ncbi FBXW7/hCDC4 is a general tumor suppressor in human cancer
    Shahab Akhoondi
    Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden
    Cancer Res 67:9006-12. 2007
    ..Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer...
  47. ncbi The polycomb protein Pc2 is a SUMO E3
    Michael H Kagey
    Department of Biochemistry and Molecular Genetics, Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA
    Cell 113:127-37. 2003
    ..These results demonstrate that Pc2 is a SUMO E3, and suggest that PcG bodies may be sumoylation centers...
  48. pmc PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0
    Roger D Everett
    MRC Virology Unit, Church Street, Glasgow G11 5JR, Scotland, United Kingdom
    J Virol 80:7995-8005. 2006
    ..We conclude that PML contributes to a cellular antiviral repression mechanism that is countered by the activity of ICP0...
  49. ncbi A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1
    Jianping Jin
    Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell 23:709-21. 2006
    ..These studies uncover diverse substrate receptors for Cul4 and identify Cdt2 as a conserved component of the Cul4-Ddb1 E3 that is essential to destroy Cdt1 and ensure proper cell cycle regulation of DNA replication...
  50. ncbi Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex
    B A Schulman
    Cellular Biochemistry and Biophysics Program, Medical Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Nature 408:381-6. 2000
    ....
  51. pmc Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase
    S Nakagawa
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08855, USA
    Mol Cell Biol 20:8244-53. 2000
    ....
  52. ncbi Chaperoned ubiquitylation--crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex
    Minghao Zhang
    Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom
    Mol Cell 20:525-38. 2005
    ....
  53. ncbi An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast
    R Ciosk
    Research Institute of Molecular Pathology, Vienna, Austria
    Cell 93:1067-76. 1998
    ..We propose that the APC promotes sister separation not by destroying cohesins but instead by liberating the "sister-separating" Esp1 protein from its inhibitor Pds1p...
  54. ncbi Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation
    Markus Welcker
    Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Mol Cell 12:381-92. 2003
    ..Thus, cyclin E turnover is controlled by multiple biological inputs and cannot be understood in terms of autophosphorylation alone...
  55. ncbi How proteolysis drives the cell cycle
    R W King
    Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA
    Science 274:1652-9. 1996
    ..Proteolysis therefore drives cell cycle progression not only by regulating CDK activity, but by directly influencing chromosome and spindle dynamics...
  56. pmc Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508
    Daisuke Morito
    Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606 8397, Japan
    Mol Biol Cell 19:1328-36. 2008
    ..Our data demonstrates that gp78 cooperates with RMA1 with E4-like activity in the ERAD of CFTRDeltaF508...
  57. ncbi Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing
    Ru Cao
    Howard Hughes Medical Institute, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599, USA
    Mol Cell 20:845-54. 2005
    ..Our results suggest that EZH2-mediated H3-K27 methylation functions upstream of PRC1 and establishes a critical role for Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing...
  58. pmc Cooperative control of striated muscle mass and metabolism by MuRF1 and MuRF2
    Christian C Witt
    Institute of Anesthesiology and Intensive Care, Universitatsklinikum Mannheim, Mannheim, Germany
    EMBO J 27:350-60. 2008
    ..Thus, combined inhibition of MuRF1/MuRF2 could provide a potent strategy to stimulate striated muscles anabolically and to protect muscles from sarcopenia during ageing...
  59. pmc CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70
    Shu Bing Qian
    Carolina Cardiovascular Biology Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Nature 440:551-5. 2006
    ....
  60. pmc Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo
    Monte S Willis
    Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599 7126, USA
    Circ Res 100:456-9. 2007
    ..These studies describe for the first time distinct and nonoverlapping functional characteristics of MuRF1 and MuRF2 in response to cardiac stress in vivo...
  61. ncbi TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity
    Michaela U Gack
    Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, Massachusetts 01772, USA
    Nature 446:916-920. 2007
    ..Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity...
  62. ncbi A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation
    H Zhu
    Department of Biochemistry and Cell Biology and Institute for Cell and Developmental Biology, State University of New York, Stony Brook 11794 5215, USA
    Nature 400:687-93. 1999
    ..Smurf1 also enhances cellular responsiveness to the Smad2 (activin/TGF-beta) pathway. Thus, targeted ubiquitination of SMADs may serve to control both embryonic development and a wide variety of cellular responses to TGF-beta signals...
  63. ncbi A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size
    Markus Welcker
    Divisions of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Curr Biol 14:1852-7. 2004
    ..We suggest that interactions between c-Myc and Fbw7gamma within the nucleolus regulate c-Myc's growth-promoting function and that c-Myc activation is likely to be an important oncogenic consequence of Fbw7 loss in cancers...
  64. ncbi Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons
    Leonard Petrucelli
    Neurogenetics Laboratory, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
    Neuron 36:1007-19. 2002
    ..Therefore, parkin and alpha-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons...
  65. ncbi E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages
    Devin E Christensen
    Department of Biochemistry, University of Washington, Box 357350, Seattle, Washington 98195 7350, USA
    Nat Struct Mol Biol 14:941-8. 2007
    ..Thus, BRCA1 has the ability to direct the synthesis of specific polyubiquitin chain linkages, depending on the E2 bound to its RING...
  66. ncbi The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover
    Lufen Chang
    Division of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, City of Hope National Medical Center, 1500 E Duarte Road, KCRB 3009, Duarte, CA 91010, USA
    Cell 124:601-13. 2006
    ..Thus, JNK antagonizes NF-kappaB during TNFalpha signaling by promoting the proteasomal elimination of c-FLIP(L)...
  67. ncbi FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation
    Markus Welcker
    Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA
    Nat Rev Cancer 8:83-93. 2008
    ..This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer...
  68. ncbi Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation
    T Ebisawa
    Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, and Research for the Future Program, the Japan Society for the Promotion of Science, 1 37 1 Kami Ikebukuro, Toshima ku, Tokyo 170 8455, Japan
    J Biol Chem 276:12477-80. 2001
    ..These results thus reveal a novel function of Smad7, i.e. induction of degradation of TbetaR-I through recruitment of an E3 ligase to the receptor...
  69. pmc Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle
    Kasia Hrecka
    Cold Spring Harbor Laboratory, Bungtown Road, Cold Spring Harbor, NY 11724, USA
    Proc Natl Acad Sci U S A 104:11778-83. 2007
    ....
  70. ncbi The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity
    Ronen Ben-Saadon
    Cancer and Vascular Biology Center, The Rappaport Faculty of Medicine and Research Institute, Technion Israel Institute of Technology, Bat Galim, Haifa 31096, Israel
    Mol Cell 24:701-11. 2006
    ..The modification is required for Ring1B ability to monoubiquitinate H2A in vitro, unraveling an as yet undescribed mechanism for ligase activation via noncanonical self-ubiquitination...
  71. ncbi CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
    Leonard Petrucelli
    Mayo Clinic, Jacksonville, FL 32224, USA
    Hum Mol Genet 13:703-14. 2004
    ..Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target...
  72. ncbi Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death
    Han Seok Ko
    Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurosci 25:7968-78. 2005
    ..Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD...
  73. pmc VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases
    Takumi Kamura
    Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi ku, Fukuoka, Fukuoka 812 8582, Japan
    Genes Dev 18:3055-65. 2004
    ..These data suggest that the functions of the Cul2-Rbx1 and Cul5-Rbx2 modules are distinct...
  74. ncbi A regulatory link between ER-associated protein degradation and the unfolded-protein response
    R Friedlander
    Max Delbruck Centrum fur Molekulare Medizin, Berlin, Germany
    Nat Cell Biol 2:379-84. 2000
    ..However, when stress is applied, the UPR is required to increase ERAD activity. We thus demonstrate, for the first time, a regulatory loop between ERAD and the UPR, which is essential for normal growth of yeast cells...
  75. pmc Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts
    Heather Mortiboys
    Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, United Kingdom
    Ann Neurol 64:555-65. 2008
    ..The aim of our study was to determine mitochondrial function and morphology in parkin-mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in parkin-mutant human tissue...
  76. ncbi F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex
    D Skowyra
    Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030, USA
    Cell 91:209-19. 1997
    ..SCF complexes couple protein kinase signaling pathways to the control of protein abundance...
  77. ncbi Biomedicine. Parkinson's--divergent causes, convergent mechanisms
    J Timothy Greenamyre
    Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
    Science 304:1120-2. 2004
  78. ncbi Ubiquitin-dependent proteolytic control of SUMO conjugates
    Kristina Uzunova
    Institute for Genetics, University of Cologne, Zulpicher Strasse 47, Cologne, Germany
    J Biol Chem 282:34167-75. 2007
    ..Simultaneous inhibition of both mechanisms leads to severe phenotypic defects...
  79. 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...
  80. pmc A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase
    J M Huibregtse
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 92:2563-7. 1995
    ....
  81. pmc Herpes simplex virus ICP0 promotes both histone removal and acetylation on viral DNA during lytic infection
    Anna R Cliffe
    Harvard Medical School, Department of Microbiology and Molecular Genetics, 200 Longwood Avenue, Boston, MA 02115, USA
    J Virol 82:12030-8. 2008
    ..This study provides evidence that ICP0 directly alters the chromatin structure of the HSV-1 genome during lytic infection, and this system will serve as a useful model for the reduction of histone load in higher eukaryotes...
  82. ncbi Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity
    Cornelia Hampe
    Neurologie et Thérapeutique Expérimentale, INSERM U679 Université Pierre and Marie Curie, Paris, France
    Hum Mol Genet 15:2059-75. 2006
    ..The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function...
  83. ncbi Inactivation of hCDC4 can cause chromosomal instability
    Harith Rajagopalan
    The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
    Nature 428:77-81. 2004
    ..Our data suggest that chromosomal instability is caused by specific genetic alterations in a large fraction of human cancers and can occur before malignant conversion...
  84. ncbi Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin
    Sathya R Sriram
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Hum Mol Genet 14:2571-86. 2005
    ....
  85. ncbi Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator
    J Michael Younger
    Department of Cell and Developmental Biology, UNC Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
    Cell 126:571-82. 2006
    ..Thus, the RMA1 and CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to monitor the folding status of CFTR and CFTR Delta F508...
  86. pmc The F-box subunit of the SCF E3 complex is encoded by a diverse superfamily of genes in Arabidopsis
    Jennifer M Gagne
    Cellular and Molecular Biology Program and the Department of Horticulture, 1575 Linden Drive, University of Wisconsin, Madison, WI 53706, USA
    Proc Natl Acad Sci U S A 99:11519-24. 2002
    ..Collectively, the data shows that Arabidopsis has exploited the SCF complex and the ubiquitin/26S proteasome pathway as a major route for cellular regulation and that a diverse array of SCF targets is likely present in plants...
  87. ncbi The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A
    M Runte
    Institut fur Humangenetik, Universitatsklinikum Essen, 45122 Essen, Germany
    Hum Mol Genet 10:2687-700. 2001
    ..As we have not obtained any evidence for other genes in this region, which, from the mouse data appears to be critical for the neonatal Prader-Willi syndrome phenotype, a lack of these snoRNAs may be causally involved in this disease...
  88. ncbi The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation
    Sovana Adhikary
    Institute for Molecular Biology and Tumor Research, University of Marburg, Emil Mannkopff Str 2, 35033 Marburg, Germany
    Cell 123:409-21. 2005
    ..Our results suggest that site-specific ubiquitination regulates the switch between an activating and a repressive state of the Myc protein, and they suggest a strategy to interfere with Myc function in vivo...
  89. ncbi The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor
    Xiaoyun Wen
    Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
    J Biol Chem 282:27046-57. 2007
    ..Vpr, thus, functions like the HIV1 proteins Vif and Vpu to usurp cellular ubiquitin ligases for viral functions...
  90. ncbi Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development
    Ryosuke Tsunematsu
    Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
    J Biol Chem 279:9417-23. 2004
    ..Expression of Notch1, -2, or -3 or of cyclin E was unaffected in Fbw7(-/-) embryos. Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development...
  91. ncbi Structure of the C-terminal RING finger from a RING-IBR-RING/TRIAD motif reveals a novel zinc-binding domain distinct from a RING
    Allan D Capili
    Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA
    J Mol Biol 340:1117-29. 2004
    ..From a comparison of the RING2 structure with those reported for RINGs, we infer sequence determinants that allow discrimination between RING2 and RING domains at the sequence analysis level...
  92. ncbi Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses
    S I Matsuzawa
    The Burnham Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA
    Mol Cell 7:915-26. 2001
    ..Expression of Siah is induced by p53, revealing a way of linking genotoxic injury to destruction of beta-catenin, thus reducing activity of Tcf/LEF transcription factors and contributing to cell cycle arrest...
  93. pmc Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase
    Y Zhang
    Laboratory of Cellular and Molecular Biology, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892, USA
    Proc Natl Acad Sci U S A 98:974-9. 2001
    ....
  94. ncbi De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome
    T Matsuura
    Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
    Nat Genet 15:74-7. 1997
    ..It may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products...
  95. pmc The disruption of ND10 during herpes simplex virus infection correlates with the Vmw110- and proteasome-dependent loss of several PML isoforms
    R D Everett
    MRC Virology Unit, Glasgow G11 5JR, Scotland
    J Virol 72:6581-91. 1998
    ..These observations provide a biochemical mechanism to explain the observed effects of Vmw110 on ND10 and suggest a simple yet powerful mechanism by which Vmw110 might function during virus infection...
  96. ncbi Diverse effects of pathogenic mutations of Parkin that catalyze multiple monoubiquitylation in vitro
    Noriyuki Matsuda
    Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo ku, Tokyo 113 8613
    J Biol Chem 281:3204-9. 2006
    ....
  97. ncbi Whose end is destruction: cell division and the anaphase-promoting complex
    W Zachariae
    Research Institute of Molecular Pathology, A 1030 Vienna, Austria
    Genes Dev 13:2039-58. 1999
  98. ncbi Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b
    K Bachmaier
    Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada
    Nature 403:211-6. 2000
    ..Cbl-b is thus a key regulator of activation thresholds in mature lymphocytes and immunological tolerance and autoimmunity...
  99. pmc The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor
    Andrea Vecchione
    Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    Mol Cell Biol 23:3363-72. 2003
    ..This is the first demonstration of regulation of stability of a tyrosine kinase receptor by the Nedd4 (HECT) family of E3 ligases...
  100. pmc Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin
    Ventzislava A Hristova
    Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada
    J Biol Chem 284:14978-86. 2009
    ..The identification of the RING0 domain in parkin provides a new overall domain structure for the protein that will be important in assessing the roles of ARJP mutations and designing experiments aimed at understanding the disease...
  101. pmc Mechanistic analysis of PCNA poly-ubiquitylation by the ubiquitin protein ligases Rad18 and Rad5
    Joanne L Parker
    Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms, Herts, UK
    EMBO J 28:3657-66. 2009
    ..Our results provide information about a unique conjugation mechanism that appears to be specialised for a regulatable pattern of dual modification...

Research Grants70

  1. Cellular &Inflammatory Pathways in Ashtma &Allergic Diseases: From IgE to Cells
    LAWRENCE BARRY SCHWARTZ; Fiscal Year: 2012
    ..Understanding more precisely the characteristics of and the mechanism(s) behind desensitization will enable physicians to better utilize this approach to reduce mast cell/basophil-mediated contributions to asthma and allergic diseases. ..
  2. REGULATION AND FUNCTION OF STE20-RELATED PROTEIN KINASES
    Melanie H Cobb; Fiscal Year: 2012
    ..Understanding the mechanisms of action of this family will provide significant insights into the control of ion balance and other essential processes, and may reveal novel strategies to develop anti-hypertensive therapies. ..
  3. Induction and maintenance of regulatory T cells
    Mitchell Kronenberg; Fiscal Year: 2013
    ..This proposal will study the mechanisms by which the immune responses are properly controlled. Such knowledge will eventually facilitate the design of novel therapeutic approaches for immunological diseases. ..
  4. Cell Cycle Regulation and Adult T Cell Leukemia
    Chou Zen Giam; Fiscal Year: 2013
    ..The study will provide molecular insights that can lead to the development of treatment strategies for human cancer ..
  5. Diverse Roles for RIC8 During G Protein Signaling in Fungi
    Katherine A Borkovich; Fiscal Year: 2012
    ....
  6. 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. ..
  7. 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. ..
  8. Molecular Pathogenesis of MDS and CMML
    Jaroslaw P Maciejewski; Fiscal Year: 2013
    ..We will precisely map these lesions, identifying genes that may play a role in the disease and potentially act as targets of therapy. ..
  9. Role of inflammation and cellular stress in the pathogenesis of type 2 diabetes
    Liangyou Rui; Fiscal Year: 2013
    ..The outcome is expected to lead to new therapies for hepatic steatosis and type 2 diabetes by targeting the NIK pathways. ..
  10. Misregulation of receptor tyrosine kinase signaling in PKD
    Jordan A Kreidberg; Fiscal Year: 2013
    ..Failure to ubquitinate c-Met is due to sequestration of the E3 ubiquitin ligase c-Cbl by 31 integrin in the Golgi apparatus. This grant will investigate the roles of c-Cbl, c-Met and protein glycosylation in the pathogenesis of PKD. ..
  11. Genetic Control of Axial Patterning in Drosophila Eye
    Amit Singh; Fiscal Year: 2010
    ..It will also help to understand the molecular basis of developmental defects caused by mutations in the human homolog of Drosophila. ..
  12. Post-translational regulation of MLL in leukemogenesis
    ANDREW GEORGE MUNTEAN; Fiscal Year: 2013
    ..These studies focus on the MLL-PAFc interaction and ubiquitination of MLL which are directly relevant to MLL and HOX dependent leukemias and may prove as effective therapeutic targets. ..
  13. Post-translational regulation of MLL in leukemogenesis
    ANDREW GEORGE MUNTEAN; Fiscal Year: 2012
    ..These studies focus on the MLL-PAFc interaction and ubiquitination of MLL which are directly relevant to MLL and HOX dependent leukemias and may prove as effective therapeutic targets. ..
  14. The Role of hPso4 in DNA Repair and Chemotherapy Resistance
    Montaser Shaheen; Fiscal Year: 2013
    ..We will deplete this E2 and evaluate if this will achieve the same chemosensitivity as depleting hPso4. This will open the opportunity to identify Ubc3 small molecule inhibitors as cancer therapy. ..
  15. REGULATION OF NUCLEAR ENVELOPE ASSEMBLY AND DISASSEMBLY
    Katherine L Wilson; Fiscal Year: 2012
    ..Aim 3 is a whole-genome and promoter-specific analysis of BAF function in C. elegans, which is expected to identify genes relevant to its roles in muscle and DNA- damage responses. ..
  16. Mechanisms of cancer initiation by TRIM32
    Molly F Kulesz-Martin; Fiscal Year: 2012
    ..abstract_text> ..
  17. Molecular and Cellular Mechanisms of IL-17 Signaling
    Xiaoxia Li; Fiscal Year: 2013
    ....
  18. Negative regulation of NF-kB and inflammation by TAX1BP1
    Edward W Harhaj; Fiscal Year: 2012
    ..This proposal will provide mechanistic insight into how TAX1BP1, Itch and A20 function together to inactivate key signaling molecules and restrict inflammatory signaling pathways. ..
  19. Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
    Jacki Kornbluth; Fiscal Year: 2013
    ..A variety of tumor models will be evaluated to determine where NKLAM plays a role. Analysis of NKLAM KO mice may reveal additional roles for NKLAM and potentially unveil alternative mechanisms of cell killing. ..
  20. Spinocerebellar Ataxia Type 2 Gene and Gene Product
    Stefan M Pulst; Fiscal Year: 2012
    ..This will allow us to test the effects of specific proteins on nerve cell dysfunction and cell death in live animals with the ultimate goal of identifying new therapeutic avenues for treatment of human neurodegenerative diseases. ..
  21. Characterizaton of Motility Factor Receptor
    Avraham Raz; Fiscal Year: 2012
    ..It is expected that these studies will lead to a better diagnosis, treatment and development of rational therapy. ..
  22. Meiosis, SUMOylation and the ZIP3 Protein: Parallel Studies in Mouse and Yeast.
    Neil Hunter; Fiscal Year: 2012
    ..Defects in these processes are linked to human infertility, miscarriage and genetic diseases, particularly cancer. A greater understanding of their mechanism and regulation will help us better understand the etiology of these diseases. ..
  23. Role of Natural Killer Lytic-Associated Molecule (NKLAM) in Natural Killer Functi
    Jacki Kornbluth; Fiscal Year: 2010
    ..These diseases are of great relevance to the health care system as the incidence of cancer is rising as the population is aging and new, resistant microbial pathogens are emerging and spreading. ..
  24. 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. ..
  25. Training/Research Center-Bone Marrow Failure Syndromes
    Jaroslaw P Maciejewski; Fiscal Year: 2013
    ..We will precisely map these lesions, identifying genes that may play a role in the disease and potentially act as targets of therapy;these studies will form the basis for the training program proposed. ..
  26. HTLV-I Tax activates the anaphase promoting complex
    Chou Zen Giam; Fiscal Year: 2013
    ..The study will provide molecular insights that can lead to the development of treatment strategies for human cancer. ..
  27. 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. ..
  28. Inflammatory Proteases, Ubiquitin Proteasome System, and Myocyte Death
    Abdelkarim Sabri; Fiscal Year: 2012
    ....
  29. Elucidating the in vivo Role of the p53 Apoptosis-Specific Target Gene Siva
    Jeanine L Frey; Fiscal Year: 2013
    ..abstract_text> ..
  30. Novel Strategies for Treatment of Myeloproliferative Disorders
    Roya Khosravi-Far; Fiscal Year: 2012
    ..abstract_text> ..
  31. Regulation of Osteoblast Function by Megakaryocytes: Key Signaling Proteins
    Melissa A Kacena; Fiscal Year: 2013
    ..Identifying the pathways that lead to enhanced bone volume in vivo will lead to the development of novel therapeutic approaches that stimulate bone formation for the treatment of osteoporosis and other bone loss diseases. ..
  32. HoxA10 Function During Myeloid Differentiation
    ELIZABETH ANN EKLUND; Fiscal Year: 2011
    ..Therefore, the goal of these studies is to identify novel targets for the treatment of myeloid malignancy. ..
  33. Modulating calcineurin signaling pathways in muscle
    Beverly A Rothermel; Fiscal Year: 2012
    ..abstract_text> ..
  34. Regulation and Role of Ornithine Decarboxylase in Cell Proliferation and Cancer
    John L Cleveland; Fiscal Year: 2013
    ..abstract_text> ..
  35. Regulation of Hepatic Carbohydrate Metabolism by STBD1
    Alan Cheng; Fiscal Year: 2012
    ..Importantly, this can ultimately identify novel therapeutic avenues in these diseases. ' ..
  36. Characterization of TGR5-D2-WSB1 signaling in metabolic homeostasis in vivo
    ANTONIO C contact BIANCO; Fiscal Year: 2010
    ..2. Tissue-specific TGR5 and WSB1 expression is critical in metabolic control. 3. Signaling through the TGR5-D2-WSB1 pathway affects cellular metabolic profile and gene expression profiles. ..
  37. CONTROL OF APOPTOSIS BY DROSOPHILA CELL DEATH GENES
    Hermann Steller; Fiscal Year: 2012
    ..Therefore, this project will have profound implications for both basic science and medicine. ..
  38. Role of Parkin in Regulating Manganese Toxicity
    JEROME ALLAN ROTH; Fiscal Year: 2010
    ..Thus, the studies proposed in this grant are relevant to human health in that they will investigate the mechanism by which mutations in the parkin gene regulate and increase vulnerability to develop manganism. ..
  39. Novel Model Systems Link Floridean Starch Metabolism to Lafora Disease
    Matthew S Gentry; Fiscal Year: 2010
    ..The findings from all three of my specific aims can be applied to identify new therapeutic targets to treat LD and possibly other polyglucosan diseases. ..
  40. 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. ..
  41. Biology of nuclear receptor rev-erb alpha in circadian rhythm and metabolism
    Lei Yin; Fiscal Year: 2011
    ..In addition, this work may shed the new light on Identifying the new therapeutic targets for treating Insulin resistance and diabetes. ..
  42. Secretory Vesicle Function During Spermatogenesis & Fertilization in C. elegans
    STEVEN W L apos HERNAULT; Fiscal Year: 2010
    ..The processes we study, in addition to functioning in sperm, also play a role in proper kidney function and bone formation. ..
  43. NUCLEAR RECEPTOR SIGNALING PATHWAYS IN ATHEROGENESIS
    PETER J TONTONOZ; Fiscal Year: 2013
    ..We will also generate and analyze lesion formation in Idol-/- human apoBTg mice. ..
  44. The Role of the Cochaperone/E3 Ubiquitin Ligase CHIP in Nuclear Stress Response
    SARAH MARIE RONNEBAUM; Fiscal Year: 2010
    ....
  45. Rest-Activated Program of Gene Expression in Ischemia
    R Suzanne Zukin; Fiscal Year: 2013
    ....
  46. Regulation of SMN and Identification of its Downstream Target
    Judith Jebanathirajah Steen; Fiscal Year: 2013
    ..abstract_text> ..
  47. Study of an iron-responsive E3 ligase regulating mammalian iron homeostasis
    Richard K Bruick; Fiscal Year: 2013
    ..To that end, this proposal describes the characterization of a candidate sensor and regulator of mammalian iron homeostasis, FBXL5. ..
  48. REGULATION OF DEFENSE SIGNALING IN TOMATO
    Gregg A Howe; Fiscal Year: 2012
    ....
  49. Enhancement of Medullary Erythropoiesis during Anemia by Trib3
    David Kuhrt; Fiscal Year: 2013
    ..This trainin plan is designed to advance impacting first author papers and expertise as a new independent investigator. ..
  50. Programmed Cell Death and Disease Resistance in Arabidopsis
    Roger W Innes; Fiscal Year: 2013
    ..Together with Specific Aims 1-3, these analyses will provide significant new insight into how PCD and immunity are regulated. ..
  51. Host-pathogen competition in IFN mediated antiviral defense
    Jae U Jung; Fiscal Year: 2013
    ....
  52. Ubiquitin-like protein modification in diabetic cardiomyopathy
    Jay Yang; Fiscal Year: 2013
    ..The significance lies in the novel hypothesis on the role of the Ub-ligase CHIP in regulating both apoptosis and autophagy, and the proposed mechanistic study of a highly clinically relevant problem. ..
  53. FLUID SHEAR STRESS SIGNAL TRANSDUCTION IN ENDOTHELIUM
    Keigi Fujiwara; Fiscal Year: 2013
    ..Elucidating the specific pathways by which protein kinase C-zeta modulates vessel function would provide the basis to develop new therapies to prevent atherosclerosis. ..
  54. Mechanism of Gli3 processing in Hedgehog signaling
    Baolin Wang; Fiscal Year: 2013
    ..The completion of the proposed studies will significantly advance our understanding of the regulation and function of Gli3 protein in Hh signaling. ..
  55. CARP-1: A Potential Therapeutic Agent for Breast Cancer
    ARUN KUMAR RISHI; Fiscal Year: 2013
    ..abstract_text> ..
  56. Asb2 in CD4+ T cell lineage differentiation and its plasticity
    Xiao Hong Sun; Fiscal Year: 2013
    ..Fresh ideas will likely emerge from these studies that will be o therapeutic value in the contest of immunity and autoimmunity. ..
  57. Hypoxia and Anticancer Drug Action
    Garth Powis; Fiscal Year: 2013
    ..abstract_text> ..
  58. Trim32 Regulation of Piasy in Skin Homeostasis
    Molly F Kulesz-Martin; Fiscal Year: 2013
    ..Ultimately, these studies may impact our understanding of the molecular mechanisms of psoriasis as distinct from atopic dermatitis and lead to rational improvement of treatment strategies for psoriasis patients. ..
  59. FINR: A Novel Modulator of Insulin Signaling
    Marc R Montminy; Fiscal Year: 2010
    ..The current proposal focuses on the role of a so- called insulin resistance protein called TRB3 in preventing the insulin signal from working in muscle and other tissues in the body. ..
  60. Indolecarbinol target proteins and anti-cancer signaling in human melanoma cells
    Gary L Firestone; Fiscal Year: 2013
    ..Our proposed studies will establish the preclinical foundation that is needed to eventually develop novel and low cost I3C-based therapeutic strategies for human skin cancers. ..
  61. Assembly and Trafficking of IK1 and SK3 in Endothelia
    Daniel C Devor; Fiscal Year: 2012
    ..Our studies will provide novel insight into how these processes can be manipulated for clinical gain. ..
  62. A Novel Carcinogen-Induced Cell Cycle Checkpoint
    Cyrus Vaziri; Fiscal Year: 2013
    ..g. Rad18 or its activating kinases) whose inhibition enhances the efficacy of existing cancer therapies. ..
  63. Quantitative Analysis of RING E3 Ubiquitin Ligases
    CHARLES M BRENNER; Fiscal Year: 2010
    ..Second, innovations in analysis of RING E3 ubiquitin ligases are necessary to understand the specificity of function of RING E3 ubiquitin ligases, which have key functions in the health of every organ system. ..
  64. TRAF6 E3 LIGASE FUNCTION IN OSTEOCLASTOGENESIS
    Bryant G Darnay; Fiscal Year: 2010
    ..In particular, the data gathered from these experiments may provide insights to developing therapeutic strategies for a variety of bone related disease and possibly other diseases associated with immunity and inflammation ..
  65. Roles of ubiquitin protein ligases in endocytosis
    Linda Hicke; Fiscal Year: 2005
    ..b>Ubiquitin protein ligases are key components of the ubiquitination machinery that recognize and modify specific plasma membrane ..
  66. MECHANISMS OF CELL CYCLE CONTROL DURING MAMMARY GLAND DE
    Hui Zhang; Fiscal Year: 2001
    ..These studies should also provide a basis to design novel strategies for diagnosis, prognosis, and therapeutic treatment of breast cancers. ..
  67. Salmonella SopA is a functional mimicry of eukaryotic E3 protein ubiquitin ligase
    Daoguo Zhou; Fiscal Year: 2010
    ..Results from this study will help us understand how Salmonella induces intestinal inflammation in humans. ..
  68. Capture of Ubiquitin Conjugation and Deconjugation Enzyme Substrates
    Robert Cohen; Fiscal Year: 2010
    ..To overcome this problem, a new approach termed cognate-complex biotin tagging ("CBiT") will be developed and applied to complexes that regulate ubiquitin-dependent signaling. ..
  69. Luciferase Screen for MDM2 E3 Ligase Inhibitors
    Brent Stockwell; Fiscal Year: 2007
    ..In addition, small molecules can sometimes be developed into therapeutic agents. In this application, we propose to screen for small molecules that inhibit MDM2 E3 ligase activity. [unreadable] [unreadable] [unreadable]..
  70. Novel Small Molecule Inhibitors of HIV
    Xiao Fang Yu; Fiscal Year: 2010
    ..We have identified a small molecule inhibitor of Vif. The overall goal of this project is to further characterize the novel small molecule Vif inhibitor and its derivatives that restore the potent innate antiviral defense. ..