Part of the Springer Theses book series (Springer Theses)


All proteins undergo a life cycle, starting from their synthesis at ribosomes and ending with their degradation to peptides and single amino acids. Thereby, the building blocks for the de novo synthesis of polypeptides are recycled and in addition important cellular functions are controlled. These include protein homoeostasis, cell proliferation, signal transduction and antigen production. The lysosomal and the non-lysosomal protein degradation pathways process the majority of intracellular self and nonself proteins.


Major Histocompatibility Complex Class Boronic Acid Core Particle Inclusion Body Myositis Transporter Associate With Antigen Processing 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    D. Finley, Recognition and processing of ubiquitin-protein conjugates by the proteasome. Ann. Rev. Biochem. 78, 477–513 (2009)CrossRefGoogle Scholar
  2. 2.
    A.L. Goldberg, K.L. Rock, Proteolysis, proteasomes and antigen presentation. Nature 357, 375–379 (1992)CrossRefGoogle Scholar
  3. 3.
    J.D. Etlinger, A.L. Goldberg, A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proc. Natl. Acad. Sci. U.S.A 74, 54–58 (1977)Google Scholar
  4. 4.
    A. Hershko, A. Ciechanover, The ubiquitin system. Ann. Rev. Biochem. 67, 425–479 (1998)Google Scholar
  5. 5.
    I.A. York, S.C. Chang, T. Saric, J.A. Keys, J.M. Favreau, A.L. Goldberg, K.L. Rock, The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues. Nat. Immunol. 3, 1177–1184 (2002)Google Scholar
  6. 6.
    K.L. Rock, I.A. York, A.L. Goldberg, Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat. Immunol. 5, 670–677 (2004)Google Scholar
  7. 7.
    A. Townsend, J. Trowsdale, The transporters associated with antigen presentation. Semin. Cell Biol. 4, 53–61 (1993)CrossRefGoogle Scholar
  8. 8.
    V.H. Engelhard, Structure of peptides associated with MHC class I molecules. Curr. Opin. Immunol. 6, 13–23 (1994)Google Scholar
  9. 9.
    K. Falk, O. Rotzschke, S. Stevanovic, G. Jung, H.G. Rammensee, Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351, 290–296 (1991)Google Scholar
  10. 10.
    J.M. Vyas, A.G. Van der Veen, H.L. Ploegh, The known unknowns of antigen processing and presentation. Nat. Rev. Immunol. 8, 607–618 (2008)Google Scholar
  11. 11.
    J. Neefjes, M.L. Jongsma, P. Paul, O. Bakke, Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat. Rev. Immunol. 11, 823–836 (2011)Google Scholar
  12. 12.
    C.M. Pickart, Mechanisms underlying ubiquitination. Ann. Rev. Biochem. 70, 503–533 (2001)CrossRefGoogle Scholar
  13. 13.
    J.M. Berg, J.L. Tymoczko, L. Stryer, Biochemistry (W H Freeman, New York, 2002)Google Scholar
  14. 14.
    D. Voges, P. Zwickl, W. Baumeister, The 26S proteasome: a molecular machine designed for controlled proteolysis. Ann. Rev. Biochem. 68, 1015–1068 (1999)CrossRefGoogle Scholar
  15. 15.
    M. Bochtler, L. Ditzel, M. Groll, R. Huber, Crystal structure of heat shock locus V (HslV) from Escherichia coli. Proc. Natl. Acad. Sci. U.S.A 94, 6070–6074 (1997)CrossRefGoogle Scholar
  16. 16.
    J. Löwe, D. Stock, B. Jap, P. Zwickl, W. Baumeister, R. Huber, Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 Å resolution. Science 268, 533–539 (1995)CrossRefGoogle Scholar
  17. 17.
    M. Groll, L. Ditzel, J. Löwe, D. Stock, M. Bochtler, H.D. Bartunik, R. Huber, Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 386, 463–471 (1997)CrossRefGoogle Scholar
  18. 18.
    P. Zwickl, A. Grziwa, G. Puhler, B. Dahlmann, F. Lottspeich, W. Baumeister, Primary structure of the Thermoplasma proteasome and its implications for the structure, function, and evolution of the multicatalytic proteinase. Biochemistry 31, 964–972 (1992)CrossRefGoogle Scholar
  19. 19.
    M. Unno, T. Mizushima, Y. Morimoto, Y. Tomisugi, K. Tanaka, N. Yasuoka, T. Tsukihara (2002). The structure of the mammalian 20S proteasome at 2.75 Å resolution, Structure, 10, 609-618Google Scholar
  20. 20.
    M. Groettrup, R. Kraft, S. Kostka, S. Standera, R. Stohwasser, P.M. Kloetzel, A third interferon-gamma-induced subunit exchange in the 20S proteasome. Eur. J. Immunol. 26, 863–869 (1996)Google Scholar
  21. 21.
    S. Murata, K. Sasaki, T. Kishimoto, S. Niwa, H. Hayashi, Y. Takahama, K. Tanaka, Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316, 1349–1353 (2007)Google Scholar
  22. 22.
    E.M. Huber, M. Groll, Inhibitors for the immuno- and constitutive proteasome: current and future trends in drug development. Angew. Chem. Int. Ed. Engl. 51, 8708–8720 (2012)CrossRefGoogle Scholar
  23. 23.
    K. Tanaka, T. Yoshimura, T. Tamura, T. Fujiwara, A. Kumatori, A. Ichihara, Possible mechanism of nuclear translocation of proteasomes. FEBS Lett. 271, 41–46 (1990)CrossRefGoogle Scholar
  24. 24.
    M. Groll, M. Bajorek, A. Köhler, L. Moroder, D.M. Rubin, R. Huber, M.H. Glickman, D. Finley, A gated channel into the proteasome core particle. Nat. Struct. Biol. 7, 1062–1067 (2000)Google Scholar
  25. 25.
    F.G. Whitby, E.I. Masters, L. Kramer, J.R. Knowlton, Y. Yao, C.C. Wang, C.P. Hill, Structural basis for the activation of 20S proteasomes by 11S regulators. Nature 408, 115–120 (2000)Google Scholar
  26. 26.
    B.M. Stadtmueller, C.P. Hill, Proteasome activators. Mol. Cell 41, 8–19 (2011)CrossRefGoogle Scholar
  27. 27.
    P.C. Ramos, J. Hockendorff, E.S. Johnson, A. Varshavsky, R.J. Dohmen, Ump1p is required for proper maturation of the 20S proteasome and becomes its substrate upon completion of the assembly. Cell 92, 489–499 (1998)CrossRefGoogle Scholar
  28. 28.
    M. Groll, W. Heinemeyer, S. Jäger, T. Ullrich, M. Bochtler, D.H. Wolf, R. Huber, The catalytic sites of 20S proteasomes and their role in subunit maturation: a mutational and crystallographic study. Proc. Natl. Acad. Sci. U.S.A 96, 10976–10983 (1999)CrossRefGoogle Scholar
  29. 29.
    L. Ditzel, R. Huber, K. Mann, W. Heinemeyer, D.H. Wolf, M. Groll, Conformational constraints for protein self-cleavage in the proteasome. J. Mol. Biol. 279, 1187–1191 (1998)CrossRefGoogle Scholar
  30. 30.
    M. Groettrup, C.J. Kirk, M. Basler, Proteasomes in immune cells: more than peptide producers? Nat. Rev. Immunol. 10, 73–78 (2010)CrossRefGoogle Scholar
  31. 31.
    M. Aki, N. Shimbara, M. Takashina, K. Akiyama, S. Kagawa, T. Tamura, N. Tanahashi, T. Yoshimura, K. Tanaka, A. Ichihara, Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. J. Biochem. 115, 257–269 (1994)Google Scholar
  32. 32.
    T.A. Griffin, D. Nandi, M. Cruz, H.J. Fehling, L.V. Kaer, J.J. Monaco, R.A. Colbert, Immunoproteasome assembly: cooperative incorporation of interferon gamma (IFN-gamma)-inducible subunits. J. Exp. Med. 187, 97–104 (1998)CrossRefGoogle Scholar
  33. 33.
    C. Realini, W. Dubiel, G. Pratt, K. Ferrell, M. Rechsteiner, Molecular cloning and expression of a gamma-interferon-inducible activator of the multicatalytic protease. J. Biol. Chem. 269, 20727–20732 (1994)Google Scholar
  34. 34.
    M. Rechsteiner, C.P. Hill, Mobilizing the proteolytic machine: cell biological roles of proteasome activators and inhibitors. Trends Cell Biol. 15, 27–33 (2005)CrossRefGoogle Scholar
  35. 35.
    M. Rechsteiner, C. Realini, V. Ustrell, The proteasome activator 11 S REG (PA28) and class I antigen presentation. Biochem. J. 345(Pt 1), 1–15 (2000)CrossRefGoogle Scholar
  36. 36.
    B. Guillaume, J. Chapiro, V. Stroobant, D. Colau, B. Van Holle, G. Parvizi, M.P. Bousquet-Dubouch, I. Theate, N. Parmentier, B.J. Van den Eynde, Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules. Proc. Natl. Acad. Sci. U.S.A 107, 18599–18604 (2010)CrossRefGoogle Scholar
  37. 37.
    N. Klare, M. Seeger, K. Janek, P.R. Jungblut, B. Dahlmann, Intermediate-type 20 S proteasomes in HeLa cells: “asymmetric” subunit composition, diversity and adaptation. J. Mol. Biol. 373, 1–10 (2007)CrossRefGoogle Scholar
  38. 38.
    M. Groll, M. Bochtler, H. Brandstetter, T. Clausen, R. Huber, Molecular machines for protein degradation. ChemBioChem 6, 222–256 (2005)CrossRefGoogle Scholar
  39. 39.
    E. Huber, M. Basler, R. Schwab, W. Heinemeyer, C.J. Kirk, M. Groettrup, M. Groll, Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell 148, 727–738 (2012)CrossRefGoogle Scholar
  40. 40.
    C. Cardozo, R.A. Kohanski, Altered properties of the branched chain amino acid-preferring activity contribute to increased cleavages after branched chain residues by the “immunoproteasome”. J. Biol. Chem. 273, 16764–16770 (1998)Google Scholar
  41. 41.
    M. Orlowski, C. Cardozo, C. Michaud, Evidence for the presence of five distinct proteolytic components in the pituitary multicatalytic proteinase complex. Properties of two components cleaving bonds on the carboxyl side of branched chain and small neutral amino acids. Biochemistry 32, 1563–1572 (1993)Google Scholar
  42. 42.
    M. Gaczynska, K.L. Rock, A.L. Goldberg, Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365, 264–267 (1993)Google Scholar
  43. 43.
    J. Driscoll, M.G. Brown, D. Finley, J.J. Monaco, MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature 365, 262–264 (1993)Google Scholar
  44. 44.
    B.J. Van den Eynde, S. Morel, Differential processing of class-I-restricted epitopes by the standard proteasome and the immunoproteasome. Curr. Opin. Immunol. 13, 147–153 (2001)Google Scholar
  45. 45.
    S. Murata, Y. Takahama, K. Tanaka, Thymoproteasome: probable role in generating positively selecting peptides. Curr. Opin. Immunol. 20, 192–196 (2008)Google Scholar
  46. 46.
    E.Z. Kincaid, J.W. Che, I. York, H. Escobar, E. Reyes-Vargas, J.C. Delgado, R.M. Welsh, M.L. Karow, A.J. Murphy, D.M. Valenzuela, G.D. Yancopoulos, K.L. Rock, Mice completely lacking immunoproteasomes show major changes in antigen presentation. Nat. Immunol. 13, 129–135 (2011)CrossRefGoogle Scholar
  47. 47.
    T. Muchamuel, M. Basler, M. A. Aujay, E. Suzuki, K.W. Kalim, C. Lauer, C. Sylvain, E.R. Ring, J. Shields, J. Jiang, P. Shwonek, F. Parlati, S.D. Demo, M.K. Bennett, C.J. Kirk, M. Groettrup, A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med. 15, 781–787 (2009)Google Scholar
  48. 48.
    U. Seifert, L.P. Bialy, F. Ebstein, D. Bech-Otschir, A. Voigt, F. Schroter, T. Prozorovski, N. Lange, J. Steffen, M. Rieger, U. Kuckelkorn, O. Aktas, P.M. Kloetzel, E. Kruger, Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142, 613–624 (2010)CrossRefGoogle Scholar
  49. 49.
    N.R. Gascoigne, E. Palmer, Signaling in thymic selection. Curr. Opin. Immunol. 23, 207–212 (2011)CrossRefGoogle Scholar
  50. 50.
    M.J. Bevan, Immunology. The cutting edge of T cell selection. Science 316, 1291–1292 (2007)CrossRefGoogle Scholar
  51. 51.
    P.M. Voorhees, E.C. Dees, B. O’Neil, R.Z. Orlowski, The proteasome as a target for cancer therapy. Clin. Cancer Res. 9, 6316–6325 (2003)Google Scholar
  52. 52.
    L.R. Dick, P.E. Fleming, Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov. Today 15, 243–249 (2010)Google Scholar
  53. 53.
    D.J. McConkey, K. Zhu, Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist. Updat. 11, 164–179 (2008)Google Scholar
  54. 54.
    S.T. Nawrocki, J.S. Carew, K. Dunner Jr., L.H. Boise, P.J. Chiao, P. Huang, J.L. Abbruzzese, D.J. McConkey, Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res. 65, 11510–11519 (2005)Google Scholar
  55. 55.
    E.A. Obeng, L.M. Carlson, D.M. Gutman, W.J. Harrington Jr., K.P. Lee, L.H. Boise, Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107, 4907–4916 (2006)Google Scholar
  56. 56.
    G. Bianchi, L. Oliva, P. Cascio, N. Pengo, F. Fontana, F. Cerruti, A. Orsi, E. Pasqualetto, A. Mezghrani, V. Calbi, G. Palladini, N. Giuliani, K.C. Anderson, R. Sitia, S. Cenci, The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood 113, 3040–3049 (2009)Google Scholar
  57. 57.
    T. Mujtaba, Q.P. Dou, Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov. Med. 12, 471–480 (2011)Google Scholar
  58. 58.
    I. Nickeleit, S. Zender, F. Sasse, R. Geffers, G. Brandes, I. Sorensen, H. Steinmetz, S. Kubicka, T. Carlomagno, D. Menche, I. Gutgemann, J. Buer, A. Gossler, M.P. Manns, M. Kalesse, R. Frank, N.P. Malek, Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition. Cancer Cell 14, 23–35 (2008)CrossRefGoogle Scholar
  59. 59.
    W. Lee, K.B. Kim, The immunoproteasome: an emerging therapeutic target. Curr. Top. Med. Chem. 11, 2923–2930 (2011)Google Scholar
  60. 60.
    Y.K. Ho, P. Bargagna-Mohan, M. Wehenkel, R. Mohan, K.B. Kim, LMP2-specific inhibitors: chemical genetic tools for proteasome biology. Chem. Biol. 14, 419–430 (2007)Google Scholar
  61. 61.
    M. Mishto, E. Bellavista, A. Santoro, A. Stolzing, C. Ligorio, B. Nacmias, L. Spazzafumo, M. Chiappelli, F. Licastro, S. Sorbi, A. Pession, T. Ohm, T. Grune, C. Franceschi, Immunoproteasome and LMP2 polymorphism in aged and Alzheimer’s disease brains. Neurobiol. Aging 27, 54–66 (2006)CrossRefGoogle Scholar
  62. 62.
    M. Diaz-Hernandez, F. Hernandez, E. Martin-Aparicio, P. Gomez-Ramos, M.A. Moran, J.G. Castano, I. Ferrer, J. Avila, J.J. Lucas, Neuronal induction of the immunoproteasome in Huntington’s disease. J. Neurosci. 23, 11653–11661 (2003)Google Scholar
  63. 63.
    K. Puttaparthi, J.L. Elliott, Non-neuronal induction of immunoproteasome subunits in an ALS model: possible mediation by cytokines. Exp. Neurol. 196, 441–451 (2005)CrossRefGoogle Scholar
  64. 64.
    L.R. Fitzpatrick, J.S. Small, L.S. Poritz, K.J. McKenna, W.A. Koltun, Enhanced intestinal expression of the proteasome subunit low molecular mass polypeptide 2 in patients with inflammatory bowel disease. Dis. Colon Rectum 50, 337–348; discussion 348–350 (2007)Google Scholar
  65. 65.
    T. Egerer, L. Martinez-Gamboa, A. Dankof, B. Stuhlmuller, T. Dorner, V. Krenn, K. Egerer, P.E. Rudolph, G.R. Burmester, E. Feist, Tissue-specific up-regulation of the proteasome subunit beta5i (LMP7) in Sjogren’s syndrome. Arthritis Rheum. 54, 1501–1508 (2006)CrossRefGoogle Scholar
  66. 66.
    I. Ferrer, B. Martin, J.G. Castano, J.J. Lucas, D. Moreno, M. Olive, Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis. J. Neuropathol. Exp. Neurol. 63, 484–498 (2004)Google Scholar
  67. 67.
    Z. Yang, D. Gagarin, G. St Laurent 3rd, N. Hammell, I. Toma, C.A. Hu, A. Iwasa, T.A. McCaffrey, Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome. Arterioscler. Thromb. Vasc. Biol. 29, 1213–1219 (2009)Google Scholar
  68. 68.
    A. Visekruna, N. Slavova, S. Dullat, J. Grone, A.J. Kroesen, J.P. Ritz, H.J. Buhr, U. Steinhoff, Expression of catalytic proteasome subunits in the gut of patients with Crohn’s disease. Int. J. Colorectal Dis. 24, 1133–1139 (2009)CrossRefGoogle Scholar
  69. 69.
    L.R. Fitzpatrick, V. Khare, J.S. Small, W.A. Koltun, Dextran sulfate sodium-induced colitis is associated with enhanced low molecular mass polypeptide 2 (LMP2) expression and is attenuated in LMP2 knockout mice. Dig. Dis. Sci. 51, 1269–1276 (2006)CrossRefGoogle Scholar
  70. 70.
    H.T. Ichikawa, T. Conley, T. Muchamuel, J. Jiang, S. Lee, T. Owen, J. Barnard, S. Nevarez, B.I. Goldman, C.J. Kirk, R.J. Looney, J.H. Anolik, Novel proteasome inhibitors have a beneficial effect in murine lupus via the dual inhibition of type i interferon and autoantibody secreting cells. Arthritis Rheum. 64, 493–503 (2011)Google Scholar
  71. 71.
    M. Basler, M. Dajee, C. Moll, M. Groettrup, C.J. Kirk, Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J. Immunol. 185, 634–641 (2010)Google Scholar
  72. 72.
    Y. Nagayama, M. Nakahara, M. Shimamura, I. Horie, K. Arima, N. Abiru, Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto’s thyroiditis, but not for Graves’ hyperthyroidism, in mice. Clin. Exp. Immunol. 168, 268–273 (2012)Google Scholar
  73. 73.
    D.J. Kuhn, S.A. Hunsucker, Q. Chen, P.M. Voorhees, M. Orlowski, R.Z. Orlowski, Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood 113, 4667–4676 (2009)Google Scholar
  74. 74.
    A.V. Singh, M. Bandi, M.A. Aujay, C.J. Kirk, D.E. Hark, N. Raje, D. Chauhan, K.C. Anderson, PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo. Br. J. Haematol. 152, 155–163 (2011)Google Scholar
  75. 75.
    F. Parlati, S.J. Lee, M. Aujay, E. Suzuki, K. Levitsky, J.B. Lorens, D.R. Micklem, P. Ruurs, C. Sylvain, Y. Lu, K.D. Shenk, M.K. Bennett, Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 114, 3439–3447 (2009)CrossRefGoogle Scholar
  76. 76.
    A. Vinitsky, C. Michaud, J.C. Powers, M. Orlowski, Inhibition of the chymotrypsin-like activity of the pituitary multicatalytic proteinase complex. Biochemistry 31, 9421–9428 (1992)CrossRefGoogle Scholar
  77. 77.
    M. Bogyo, J.S. McMaster, M. Gaczynska, D. Tortorella, A.L. Goldberg, H. Ploegh, Covalent modification of the active site threonine of proteasomal beta subunits and the Escherichia coli homolog HslV by a new class of inhibitors. Proc. Natl. Acad. Sci. U.S.A 94, 6629–6634 (1997)CrossRefGoogle Scholar
  78. 78.
    M. Groll, B. Schellenberg, A.S. Bachmann, C.R. Archer, R. Huber, T.K. Powell, S. Lindow, M. Kaiser, R. Dudler, A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism. Nature 452, 755–758 (2008)CrossRefGoogle Scholar
  79. 79.
    M. Groll, R. Huber, B.C. Potts, Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J. Am. Chem. Soc. 128, 5136–5141 (2006)CrossRefGoogle Scholar
  80. 80.
    M. Groll, B.C. Potts, Proteasome structure, function, and lessons learned from beta-lactone inhibitors. Curr. Top. Med. Chem. 11, 2850–2878 (2011)CrossRefGoogle Scholar
  81. 81.
    M. Groll, K.B. Kim, N. Kairies, R. Huber, C.M. Crews, Crystal structure of epoxomicin: 20S proteasome reveals a molecular basis for selectivity of α′, β′-epoxyketone proteasome inhibitors. J. Am. Chem. Soc. 122, 1237–1238 (2000)Google Scholar
  82. 82.
    K.B. Kim, J. Myung, N. Sin, C.M. Crews, Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency. Bioorg. Med. Chem. Lett. 9, 3335–3340 (1999)Google Scholar
  83. 83.
    M.A. Gräwert, N. Gallastegui, M. Stein, B. Schmidt, P.M. Kloetzel, R. Huber, M. Groll, Elucidation of the alpha-keto-aldehyde binding mechanism: a lead structure motif for proteasome inhibition. Angew. Chem. Int. Ed. Engl. 50, 542–544 (2011)CrossRefGoogle Scholar
  84. 84.
    L. Borissenko, M. Groll, 20S proteasome and its inhibitors: crystallographic knowledge for drug development. Chem. Rev. 107, 687–717 (2007)CrossRefGoogle Scholar
  85. 85.
    R.C. Kane, P.F. Bross, A.T. Farrell, R. Pazdur, Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8, 508–513 (2003)CrossRefGoogle Scholar
  86. 86.
    I. Tzvetanov, M. Spaggiari, J. Joseph, H. Jeon, J. Thielke, J. Oberholzer, E. Benedetti, The use of bortezomib as a rescue treatment for acute antibody-mediated rejection: report of three cases and review of literature. Transplant. Proc. 44, 2971–2975 (2012)CrossRefGoogle Scholar
  87. 87.
    M. Escobar, M. Velez, A. Belalcazar, E.S. Santos, L.E. Raez, The role of proteasome inhibition in nonsmall cell lung cancer. J. Biomed. Biotechnol. 2011, 806506 (2011)CrossRefGoogle Scholar
  88. 88.
    M. Groll, C.R. Berkers, H.L. Ploegh, H. Ovaa, Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 14, 451–456 (2006)CrossRefGoogle Scholar
  89. 89.
    S. Arastu-Kapur, J.L. Anderl, M. Kraus, F. Parlati, K.D. Shenk, S.J. Lee, T. Muchamuel, M.K. Bennett, C. Driessen, A.J. Ball, C.J. Kirk, Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin. Cancer Res. 17, 2734–2743 (2011)CrossRefGoogle Scholar
  90. 90.
    P. Moreau, P.G. Richardson, M. Cavo, R.Z. Orlowski, J.F. San Miguel, A. Palumbo, J.L. Harousseau, Proteasome inhibitors in multiple myeloma: 10 years later. Blood 120, 947–959 (2012)CrossRefGoogle Scholar
  91. 91.
    S. Kumar, S.V. Rajkumar, Many facets of bortezomib resistance/susceptibility. Blood 112, 2177–2178 (2008)CrossRefGoogle Scholar
  92. 92.
    D. Chauhan, G. Li, R. Shringarpure, K. Podar, Y. Ohtake, T. Hideshima, K.C. Anderson, Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 63, 6174–6177 (2003)Google Scholar
  93. 93.
    R. Oerlemans, N.E. Franke, Y.G. Assaraf, J. Cloos, I. van Zantwijk, C.R. Berkers, G.L. Scheffer, K. Debipersad, K. Vojtekova, C. Lemos, J.W. van der Heijden, B. Ylstra, G.J. Peters, G.L. Kaspers, B.A. Dijkmans, R.J. Scheper, G. Jansen, Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112, 2489–2499 (2008)Google Scholar
  94. 94.
    S. Lu, J. Yang, Z. Chen, S. Gong, H. Zhou, X. Xu, J. Wang, Different mutants of PSMB5 confer varying bortezomib resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. Exp. Hematol. 37, 831–837 (2009)Google Scholar
  95. 95.
    N.E. Franke, D. Niewerth, Y.G. Assaraf, J. van Meerloo, K. Vojtekova, C.H. van Zantwijk, S. Zweegman, E.T. Chan, C.J. Kirk, D.P. Geerke, A.D. Schimmer, G.J. Kaspers, G. Jansen, J. Cloos, Impaired bortezomib binding to mutant beta5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia 26, 757–768 (2011)Google Scholar
  96. 96.
    E. Suzuki, S. Demo, E. Deu, J. Keats, S. Arastu-Kapur, P.L. Bergsagel, M.K. Bennett, C.J. Kirk, Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PLoS One 6, e27996 (2011)Google Scholar
  97. 97.
    K. Fostier, A. De Becker, R. Schots, Carfilzomib: a novel treatment in relapsed and refractory multiple myeloma. OncoTargets Ther. 5, 237–244 (2012)Google Scholar
  98. 98.
    S.D. Demo, C.J. Kirk, M.A. Aujay, T.J. Buchholz, M. Dajee, M.N. Ho, J. Jiang, G.J. Laidig, E.R. Lewis, F. Parlati, K.D. Shenk, M.S. Smyth, C.M. Sun, M.K. Vallone, T.M. Woo, C.J. Molineaux, M.K. Bennett, Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 67, 6383–6391 (2007)CrossRefGoogle Scholar
  99. 99.
    A.M. Ruschak, M. Slassi, L.E. Kay, A.D. Schimmer, Novel proteasome inhibitors to overcome bortezomib resistance. J. Natl Cancer Inst. 103, 1007–1017 (2011)CrossRefGoogle Scholar
  100. 100.
    H.J. Zhou, M.A. Aujay, M.K. Bennett, M. Dajee, S.D. Demo, Y. Fang, M.N. Ho, J. Jiang, C.J. Kirk, G.J. Laidig, E.R. Lewis, Y. Lu, T. Muchamuel, F. Parlati, E. Ring, K.D. Shenk, J. Shields, P.J. Shwonek, T. Stanton, C.M. Sun, C. Sylvain, T.M. Woo, J. Yang, Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J. Med. Chem. 52, 3028–3038 (2009)CrossRefGoogle Scholar
  101. 101.
    A.C. Mirabella, A.A. Pletnev, S.L. Downey, B.I. Florea, T.B. Shabaneh, M. Britton, M. Verdoes, D.V. Filippov, H.S. Overkleeft, A.F. Kisselev, Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib. Chem. Biol. 18, 608–618 (2011)CrossRefGoogle Scholar
  102. 102.
    K.W. Kalim, M. Basler, C.J. Kirk, M. Groettrup, Immunoproteasome Subunit LMP7 Deficiency and Inhibition Suppresses Th1 and Th17 but Enhances Regulatory T Cell Differentiation. J. Immunol. 189, 4182–4193 (2012)CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Chair of BiochemistryTechnische Universität MünchenGarchingGermany

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