Dysfunction of the ubiquitin–proteasome system in multiple disease conditions: therapeutic approaches

The ubiquitin–proteasome system (UPS) is the major proteolytic pathway that degrades intracellular proteins in a regulated manner. Deregulation of the UPS has been implicated in the pathogenesis of many neurodegenerative disorders like Alzheimer's disease, Parkinson's diseases, Huntington disease, Prion‐like lethal disorders, in the pathogenesis of several genetic diseases including cystic fibrosis, Angelman's syndrome and Liddle syndrome and in many cancers. Multiple lines of evidence have already proved that UPS has the potential to be an exciting novel therapeutic target for the treatment of these diseases. Here I review how aberrant functions of various genes have implicated UPS in many human disorders including neurodegeneration and cancers. I also discuss the finding that some proteasome inhibitors possess a therapeutic potential as drugs against many such diseases. BioEssays 30:1172–1184, 2008. © 2008 Wiley Periodicals, Inc.

[1]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[2]  A. Ciechanover.  The ubiquitin proteolytic system , 2006, Neurology.

[3]  P. Richardson,et al.  Bortezomib: proteasome inhibition as an effective anticancer therapy. , 2006, Annual review of medicine.

[4]  Hey-Kyoung Lee,et al.  Constructing a road map from synapses to behaviour , 2009, EMBO reports.

[5]  J. Trojanowski,et al.  Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions* , 2002, The Journal of Biological Chemistry.

[6]  A. Ciechanover,et al.  Narrative Review: Protein Degradation and Human Diseases: The Ubiquitin Connection , 2006, Annals of Internal Medicine.

[7]  G. Hayward,et al.  The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. , 2005, Immunity.

[8]  J. Collinge,et al.  Disease-associated prion protein oligomers inhibit the 26S proteasome. , 2007, Molecular cell.

[9]  S Omura,et al.  The proteasome is involved in angiogenesis. , 1998, Biochemical and biophysical research communications.

[10]  T. Ohta,et al.  The RING Heterodimer BRCA1-BARD1 Is a Ubiquitin Ligase Inactivated by a Breast Cancer-derived Mutation* , 2001, The Journal of Biological Chemistry.

[11]  A. Spada,et al.  Polyglutamines Placed into Context , 2003, Neuron.

[12]  G. Bates,et al.  Huntingtin and the molecular pathogenesis of Huntington's disease , 2004, EMBO reports.

[13]  Hugo Vanderstichele,et al.  Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein , 1998, Nature.

[14]  J. Adams.  The proteasome: a suitable antineoplastic target , 2004, Nature Reviews Cancer.

[15]  A. Fink.  Chaperone-mediated protein folding. , 1999, Physiological reviews.

[16]  Honglin Li,et al.  Proteasome inhibition induces both pro- and anti-cell death pathways in prostate cancer cells. , 2006, Cancer letters.

[17]  J. Berenson,et al.  A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma , 2007, Clinical Cancer Research.

[18]  S. Fang,et al.  RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Harry T Orr,et al.  Mutation of the E6-AP Ubiquitin Ligase Reduces Nuclear Inclusion Frequency While Accelerating Polyglutamine-Induced Pathology in SCA1 Mice , 1999, Neuron.

[20]  Shyamal K. Das,et al.  Wilson's disease: an update , 2006, Nature Clinical Practice Neurology.

[21]  N. Hattori,et al.  Pathogenetic mechanisms of parkin in Parkinson's disease , 2004, The Lancet.

[22]  K. Anderson,et al.  Intracellular Protein Degradation and Its Therapeutic Implications , 2005, Clinical Cancer Research.

[23]  D. Price,et al.  Mutant genes in familial Alzheimer's disease and transgenic models. , 1998, Annual review of neuroscience.

[24]  R. Tanzi,et al.  Endoproteolytic Cleavage and Proteasomal Degradation of Presenilin 2 in Transfected Cells* , 1997, The Journal of Biological Chemistry.

[25]  Bertrand Friguet,et al.  Antiviral Activity of the Proteasome on Incoming Human Immunodeficiency Virus Type 1 , 1998, Journal of Virology.

[26]  C. Horbinski,et al.  Proteasome inhibitors suppress formation of polyglutamine‐induced nuclear inclusions in cultured postmitotic neurons , 2004, Journal of neurochemistry.

[27]  A. Goldberg,et al.  Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. , 2006, Journal of the American Society of Nephrology : JASN.

[28]  P. Elliott,et al.  Correction: Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts , 2002, Molecular Cancer Therapeutics.

[29]  Yang Yang,et al.  Proteasome inhibitor PS‐341 induces growth arrest and apoptosis of non‐small cell lung cancer cells via the JNK/c‐Jun/AP‐1 signaling , 2004, Cancer science.

[30]  A. Ciechanover.  The ubiquitin proteolytic system and pathogenesis of human diseases: a novel platform for mechanism-based drug targeting. , 2003, Biochemical Society transactions.

[31]  K. Takata,et al.  Proteasome inhibitors protect against degeneration of nigral dopaminergic neurons in hemiparkinsonian rats. , 2005, Journal of pharmacological sciences.

[32]  P. Lansbury,et al.  The UCH-L1 Gene Encodes Two Opposing Enzymatic Activities that Affect α-Synuclein Degradation and Parkinson's Disease Susceptibility , 2002, Cell.

[33]  R. Mayer,et al.  Ubiquitin and ubiquitin-like proteins as multifunctional signals , 2005, Nature Reviews Molecular Cell Biology.

[34]  Ø. Bruserud,et al.  The proteasome inhibitors bortezomib and PR‐171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells , 2007, British journal of haematology.

[35]  P. Kloetzel,et al.  Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation* , 1998, The Journal of Biological Chemistry.

[36]  A. Ciechanover,et al.  The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. , 2002, Physiological reviews.

[37]  D. Ganem,et al.  A novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition , 2001, The Journal of cell biology.

[38]  D. Cyr,et al.  From the cradle to the grave: molecular chaperones that may choose between folding and degradation , 2001, EMBO reports.

[39]  H. Yokosawa,et al.  Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development. , 2006, Current medicinal chemistry.

[40]  B. Dahlmann.  Role of proteasomes in disease , 2007, BMC Biochemistry.

[41]  P. Osmulski,et al.  Small-molecule inhibitors of proteasome activity. , 2005, Methods in molecular biology.

[42]  Liddle's syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel , 1994, Cell.

[43]  C. Ross,et al.  Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease , 2001, Nature Medicine.

[44]  K. Münger,et al.  Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. , 1989, The EMBO journal.

[45]  P. Elliott,et al.  26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer , 2001, Journal of cellular biochemistry.

[46]  Serge Benichou,et al.  Protéines Nef du VIH et K3/K5 du virus associé au sarcome de Kaposi : des « parasites » de la voie d’endocytose , 2003 .

[47]  A. Haeringen,et al.  Angelman syndrome: a review of clinical and genetic aspects , 1999, Clinical Neurology and Neurosurgery.

[48]  P. Elliott,et al.  Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. , 2001, Cancer research.

[49]  W. Mitch,et al.  Regulation of epithelial sodium channels by the ubiquitin-proteasome proteolytic pathway. , 2006, American journal of physiology. Renal physiology.

[50]  Hiroshi Yasui,et al.  A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. , 2005, Cancer cell.

[51]  A. Levine,et al.  Association of human papillomavirus types 16 and 18 E6 proteins with p53. , 1990, Science.

[52]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[53]  P. Courtoy,et al.  Lactacystin decreases amyloid‐β peptide production by inhibiting β‐secretase activity , 2006, Journal of neuroscience research.

[54]  C. Logothetis,et al.  Bortezomib as a Potential Treatment for Prostate Cancer , 2004, Cancer Research.

[55]  O. Staub,et al.  Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination , 1997, The EMBO journal.

[56]  Yasuo Ihara,et al.  Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments , 1993, Neuron.

[57]  A. Goldberg,et al.  Importance of the Different Proteolytic Sites of the Proteasome and the Efficacy of Inhibitors Varies with the Protein Substrate* , 2006, Journal of Biological Chemistry.

[58]  P. Lockhart,et al.  Parkin Protects against the Toxicity Associated with Mutant α-Synuclein Proteasome Dysfunction Selectively Affects Catecholaminergic Neurons , 2002, Neuron.

[59]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[60]  T. Sommer,et al.  ERAD: the long road to destruction , 2005, Nature Cell Biology.

[61]  U. Lopes,et al.  p53-dependent Induction of Apoptosis by Proteasome Inhibitors* , 1997, The Journal of Biological Chemistry.

[62]  Bonifati,et al.  Association between early-onset Parkinson's disease and mutations in the parkin gene. , 2000, The New England journal of medicine.

[63]  P. Elliott,et al.  The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. , 2001, Cancer research.

[64]  K. Fischbeck,et al.  Triplet repeat expansion in neuromuscular disease , 2000, Muscle & nerve.

[65]  D. Gandara,et al.  The Proteasome Inhibitor Bortezomib in Combination with Gemcitabine and Carboplatin in Advanced Non-small Cell Lung Cancer: A California Cancer Consortium Phase I Study , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[66]  T. Rapoport,et al.  Retro-translocation of proteins from the endoplasmic reticulum into the cytosol , 2002, Nature Reviews Molecular Cell Biology.

[67]  Bert Vogelstein,et al.  APC mutations occur early during colorectal tumorigenesis , 1992, Nature.

[68]  P. Elliott,et al.  Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[69]  P. Lehner,et al.  Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101‐dependent degradation , 2002, The EMBO journal.

[70]  M. Karin,et al.  Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. , 2006, The Journal of clinical investigation.

[71]  David W. Miller,et al.  L166P Mutant DJ-1, Causative for Recessive Parkinson's Disease, Is Degraded through the Ubiquitin-Proteasome System* , 2003, Journal of Biological Chemistry.

[72]  R. Kopito,et al.  Biosynthesis and degradation of CFTR. , 1999, Physiological reviews.

[73]  X. Li,et al.  High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation , 1996, Journal of virology.

[74]  C. Pickart,et al.  Ubiquitin: structures, functions, mechanisms. , 2004, Biochimica et biophysica acta.

[75]  R. Mayer,et al.  Ubiquitin in Neurodegenerative Diseases , 1993, Brain pathology.

[76]  E. Hol,et al.  Mutations in RNA: a first example of molecular misreading in Alzheimer's disease , 1998, Trends in Neurosciences.

[77]  J. Zweier,et al.  A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal , 2002, Nature.

[78]  M. Scheffner,et al.  The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53 , 1993, Cell.

[79]  S. Paul.  Polyglutamine-mediated neurodegeneration: Use of chaperones as prevention strategy , 2007, Biochemistry (Moscow).

[80]  J. Wade Harper,et al.  Drug discovery in the ubiquitin–proteasome system , 2006, Nature Reviews Drug Discovery.

[81]  T. Dawson,et al.  Role for the ubiquitin-proteasome system in Parkinson’s disease and other neurodegenerative brain amyloidoses , 2007, NeuroMolecular Medicine.

[82]  J. Mallet,et al.  Rat α‐Synuclein Interacts with Tat Binding Protein 1, a Component of the 26S Proteasomal Complex , 2000 .

[83]  F. Hartl,et al.  Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein , 2002, Science.

[84]  Tobias Jung,et al.  The proteasome and its role in nuclear protein maintenance , 2007, Experimental Gerontology.

[85]  A. Davidoff,et al.  Bortezomib inhibits angiogenesis and reduces tumor burden in a murine model of neuroblastoma. , 2007, Surgery.

[86]  P. Bunn.  The Potential Role of Proteasome Inhibitors in the Treatment of Lung Cancer , 2004, Clinical Cancer Research.

[87]  A. Gruhler,et al.  PRE2, highly homologous to the human major histocompatibility complex-linked RING10 gene, codes for a yeast proteasome subunit necessary for chrymotryptic activity and degradation of ubiquitinated proteins. , 1993, The Journal of biological chemistry.

[88]  Tom A. Rapoport,et al.  Distinct Ubiquitin-Ligase Complexes Define Convergent Pathways for the Degradation of ER Proteins , 2006, Cell.

[89]  A. Ciechanover,et al.  The ubiquitin system. , 1998, Annual review of biochemistry.

[90]  L. Bolund,et al.  Protein misfolding and degradation in genetic diseases , 1999, Human mutation.

[91]  E. Cesarman,et al.  Pathogenesis of Kaposi's sarcoma. , 2003, Hematology/oncology clinics of North America.

[92]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[93]  P. Polakis,et al.  Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[94]  P. Elliott,et al.  Proteasome inhibition: A novel mechanism to combat asthma. , 1999, The Journal of allergy and clinical immunology.

[95]  P. Corn,et al.  Role of the ubiquitin proteasome system in renal cell carcinoma , 2007, BMC Biochemistry.

[96]  J. Hodgson,et al.  Huntingtin Is Ubiquitinated and Interacts with a Specific Ubiquitin-conjugating Enzyme* , 1996, The Journal of Biological Chemistry.

[97]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[98]  T. Ouchi,et al.  Autoubiquitination of the BRCA1·BARD1 RING Ubiquitin Ligase* , 2002, The Journal of Biological Chemistry.

[99]  F. Grosveld,et al.  Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. , 1998, Science.

[100]  J. Sutcliffe,et al.  Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons , 1997, Nature Genetics.

[101]  M. Pino,et al.  Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. , 2005, Cancer research.

[102]  K. Stangl,et al.  Proteasome inhibitors: Poisons and remedies , 2008, Medicinal research reviews.

[103]  M. Lalande,et al.  UBE3A/E6-AP mutations cause Angelman syndrome , 1996, Nature Genetics.

[104]  F. Checler,et al.  Proteasome Inhibitors Prevent the Degradation of Familial Alzheimer ' s Disease-Linked Presenilin 1 and Potentiate A 1342 Recovery from Human Cells , 2007 .

[105]  C A Ross,et al.  Synphilin‐1 is present in Lewy bodies in Parkinson's disease , 2000, Annals of neurology.

[106]  S. Schwarze,et al.  Proteasome inhibition blocks caspase‐8 degradation and sensitizes prostate cancer cells to death receptor‐mediated apoptosis , 2008, The Prostate.

[107]  Chiara Brignole,et al.  Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. , 2006, Journal of the National Cancer Institute.

[108]  D. Ganem,et al.  Functional Organization of MIR2, a Novel Viral Regulator of Selective Endocytosis* , 2002, The Journal of Biological Chemistry.