1932

Abstract

Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010919-023603
2020-01-06
2024-10-15
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/60/1/annurev-pharmtox-010919-023603.html?itemId=/content/journals/10.1146/annurev-pharmtox-010919-023603&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Adams J, Kauffman M. 2004. Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 22:304–11
    [Google Scholar]
  2. 2. 
    Spano JP, Bay JO, Blay JY, Rixe O 2005. Proteasome inhibition: a new approach for the treatment of malignancies. Bull. Cancer 92:61–66
    [Google Scholar]
  3. 3. 
    Terpos E, Roussou M, Dimopoulos MA 2008. Bortezomib in multiple myeloma. Expert. Opin. Drug Metab. Toxicol. 4:639–54
    [Google Scholar]
  4. 4. 
    Utecht KN, Kolesar J. 2008. Bortezomib: a novel chemotherapeutic agent for hematologic malignancies. Am. J. Health Syst. Pharm. 65:1221–31
    [Google Scholar]
  5. 5. 
    Dick LR, Fleming PE. 2010. Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov. Today 15:243–49
    [Google Scholar]
  6. 6. 
    Koreth J, Stevenson KE, Kim HT, Garcia M, Ho VT et al. 2009. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors. Blood 114:3956–59
    [Google Scholar]
  7. 7. 
    Pearl MH, Nayak AB, Ettenger RB, Puliyanda D, Palma Diaz MF et al. 2016. Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection. Pediatr. Nephrol. 31:1341–48
    [Google Scholar]
  8. 8. 
    Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I 2017. A comparative analysis between proteasome and immunoproteasome inhibition in cellular and humoral alloimmunity. Int. Immunopharmacol. 50:48–54
    [Google Scholar]
  9. 9. 
    Boissy P, Andersen TL, Lund T, Kupisiewicz K, Plesner T, Delaisse JM 2008. Pulse treatment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity in clinically relevant conditions. Leuk. Res. 32:1661–68
    [Google Scholar]
  10. 10. 
    Zangari M, Suva LJ. 2016. The effects of proteasome inhibitors on bone remodeling in multiple myeloma. Bone 86:131–38
    [Google Scholar]
  11. 11. 
    Henninger N, Sicard KM, Bouley J, Fisher M, Stagliano NE 2006. The proteasome inhibitor VELCADE reduces infarction in rat models of focal cerebral ischemia. Neurosci. Lett. 398:300–5
    [Google Scholar]
  12. 12. 
    Zhang L, Zhang ZG, Buller B, Jiang J, Jiang Y et al. 2010. Combination treatment with VELCADE and low-dose tissue plasminogen activator provides potent neuroprotection in aged rats after embolic focal ischemia. Stroke 41:1001–7
    [Google Scholar]
  13. 13. 
    Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD et al. 2007. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110:3281–90
    [Google Scholar]
  14. 14. 
    Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A et al. 1999. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–22
    [Google Scholar]
  15. 15. 
    Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH 2003. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. PNAS 100:9946–51
    [Google Scholar]
  16. 16. 
    Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G et al. 2002. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. PNAS 99:14374–79
    [Google Scholar]
  17. 17. 
    Pei XY, Dai Y, Grant S 2003. The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. Leukemia 17:2036–45
    [Google Scholar]
  18. 18. 
    Nikrad M, Johnson T, Puthalalath H, Coultas L, Adams J, Kraft AS 2005. The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol. Cancer Ther. 4:443–49
    [Google Scholar]
  19. 19. 
    Kandasamy K, Kraft AS. 2008. Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region. Mol. Cancer Ther. 7:1091–100
    [Google Scholar]
  20. 20. 
    Chauhan D, Catley L, Li G, Podar K, Hideshima T et al. 2005. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8:407–19
    [Google Scholar]
  21. 21. 
    Lioni M, Noma K, Snyder A, Klein-Szanto A, Diehl JA et al. 2008. Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway. Mol. Cancer Ther. 7:2866–75
    [Google Scholar]
  22. 22. 
    Periyasamy-Thandavan S, Jackson WH, Samaddar JS, Erickson B, Barrett JR et al. 2010. Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER+ breast cancer cells. Autophagy 6:19–35
    [Google Scholar]
  23. 23. 
    Zang Y, Thomas SM, Chan ET, Kirk CJ, Freilino ML et al. 2012. The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4. Autophagy 8:1873–74
    [Google Scholar]
  24. 24. 
    Palombella VJ, Conner EM, Fuseler JW, Destree A, Davis JM et al. 1998. Role of the proteasome and NF-κB in streptococcal cell wall-induced polyarthritis. PNAS 95:15671–76
    [Google Scholar]
  25. 25. 
    Kalogeris TJ, Laroux FS, Cockrell A, Ichikawa H, Okayama N et al. 1999. Effect of selective proteasome inhibitors on TNF-induced activation of primary and transformed endothelial cells. Am. J. Physiol. 276:C856–64
    [Google Scholar]
  26. 26. 
    Grisham MB, Palombella VJ, Elliott PJ, Conner EM, Brand S et al. 1999. Inhibition of NF-κB activation in vitro and in vivo: role of 26S proteasome. Meth. Enzymol. 300:345–63
    [Google Scholar]
  27. 27. 
    Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C et al. 2001. Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-κB, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin. Cancer Res. 7:1419–28
    [Google Scholar]
  28. 28. 
    Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ et al. 2001. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-κB inhibition. Cancer Res 61:3535–40
    [Google Scholar]
  29. 29. 
    Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ et al. 2001. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–76
    [Google Scholar]
  30. 30. 
    Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA et al. 2001. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J. Cell Biochem. 82:110–22
    [Google Scholar]
  31. 31. 
    Ling YH, Liebes L, Jiang JD, Holland JF, Elliott PJ et al. 2003. Mechanisms of proteasome inhibitor PS-341-induced G2-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin. Cancer Res. 9:1145–54
    [Google Scholar]
  32. 32. 
    An WG, Hwang SG, Trepel JB, Blagosklonny MV 2000. Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 14:1276–83
    [Google Scholar]
  33. 33. 
    Dai Y, Rahmani M, Grant S 2003. Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-κB-dependent process. Oncogene 22:7108–22
    [Google Scholar]
  34. 34. 
    Collins GA, Goldberg AL. 2017. The logic of the 26S proteasome. Cell 169:792–806
    [Google Scholar]
  35. 35. 
    Etlinger JD, Goldberg AL. 1977. A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. PNAS 74:54–58
    [Google Scholar]
  36. 36. 
    Hershko A, Ciechanover A. 1982. Mechanisms of intracellular protein breakdown. Annu. Rev. Biochem. 51:335–64
    [Google Scholar]
  37. 37. 
    Wang X, Herr RA, Chua WJ, Lybarger L, Wiertz EJ, Hansen TH 2007. Ubiquitination of serine, threonine, or lysine residues on the cytoplasmic tail can induce ERAD of MHC-I by viral E3 ligase mK3. J. Cell Biol. 177:613–24
    [Google Scholar]
  38. 38. 
    Morozov AV, Karpov VL. 2018. Biological consequences of structural and functional proteasome diversity. Heliyon 4:e00894
    [Google Scholar]
  39. 39. 
    Dahlmann B. 2016. Mammalian proteasome subtypes: their diversity in structure and function. Arch. Biochem. Biophys. 591:132–40
    [Google Scholar]
  40. 40. 
    Hirano H, Kimura Y, Kimura A 2016. Biological significance of co- and post-translational modifications of the yeast 26S proteasome. J. Proteom. 134:37–46
    [Google Scholar]
  41. 41. 
    Tomko RJ Jr, Hochstrasser M. 2013. Molecular architecture and assembly of the eukaryotic proteasome. Annu. Rev. Biochem. 82:415–45
    [Google Scholar]
  42. 42. 
    Huber EM, Basler M, Schwab R, Heinemeyer W, Kirk CJ et al. 2012. Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell 148:727–38
    [Google Scholar]
  43. 43. 
    Harshbarger W, Miller C, Diedrich C, Sacchettini J 2015. Crystal structure of the human 20S proteasome in complex with carfilzomib. Structure 23:418–24
    [Google Scholar]
  44. 44. 
    Jager S, Groll M, Huber R, Wolf DH, Heinemeyer W 1999. Proteasome β-type subunits: unequal roles of propeptides in core particle maturation and a hierarchy of active site function. J. Mol. Biol. 291:997–1013
    [Google Scholar]
  45. 45. 
    Huber EM, Heinemeyer W, Li X, Arendt CS, Hochstrasser M, Groll M 2016. A unified mechanism for proteolysis and autocatalytic activation in the 20S proteasome. Nat. Commun. 7:10900
    [Google Scholar]
  46. 46. 
    Wang H, He Z, Xia L, Zhang W, Xu L et al. 2018. PSMB4 overexpression enhances the cell growth and viability of breast cancer cells leading to a poor prognosis. Oncol. Rep. 40:2343–52
    [Google Scholar]
  47. 47. 
    Lee GY, Haverty PM, Li L, Kljavin NM, Bourgon R et al. 2014. Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes. Cancer Res 74:3114–26
    [Google Scholar]
  48. 48. 
    Mairinger FD, Walter RF, Theegarten D, Hager T, Vollbrecht C et al. 2014. Gene expression analysis of the 26S proteasome subunit PSMB4 reveals significant upregulation, different expression and association with proliferation in human pulmonary neuroendocrine tumours. J. Cancer 5:646–54
    [Google Scholar]
  49. 49. 
    Nussbaum AK, Dick TP, Keilholz W, Schirle M, Stevanovic S et al. 1998. Cleavage motifs of the yeast 20S proteasome β subunits deduced from digests of enolase 1. PNAS 95:12504–9
    [Google Scholar]
  50. 50. 
    Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM et al. 2013. Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib. PLOS ONE 8:e53263
    [Google Scholar]
  51. 51. 
    Fricker LD, Gelman JS, Castro LM, Gozzo FC, Ferro ES 2012. Peptidomic analysis of HEK293T cells: effect of the proteasome inhibitor epoxomicin on intracellular peptides. J. Proteome Res. 11:1981–90
    [Google Scholar]
  52. 52. 
    Murata S, Takahama Y, Kasahara M, Tanaka K 2018. The immunoproteasome and thymoproteasome: functions, evolution and human disease. Nat. Immunol. 19:923–31
    [Google Scholar]
  53. 53. 
    Toes RE, Nussbaum AK, Degermann S, Schirle M, Emmerich NP et al. 2001. Discrete cleavage motifs of constitutive and immunoproteasomes revealed by quantitative analysis of cleavage products. J. Exp. Med. 194:1–12
    [Google Scholar]
  54. 54. 
    Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H et al. 2007. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316:1349–53
    [Google Scholar]
  55. 55. 
    Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K et al. 1992. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 360:597–99
    [Google Scholar]
  56. 56. 
    Kahana C, Asher G, Shaul Y 2005. Mechanisms of protein degradation: an odyssey with ODC. Cell Cycle 4:1461–64
    [Google Scholar]
  57. 57. 
    Ustrell V, Hoffman L, Pratt G, Rechsteiner M 2002. PA200, a nuclear proteasome activator involved in DNA repair. EMBO J 21:3516–25
    [Google Scholar]
  58. 58. 
    Rechsteiner M, Realini C, Ustrell V 2000. The proteasome activator 11 S REG (PA28) and class I antigen presentation. Biochem. J. 345:11–15
    [Google Scholar]
  59. 59. 
    Deshmukh FK, Yaffe D, Olshina MA, Ben-Nissan G, Sharon M 2019. The contribution of the 20S proteasome to proteostasis. Biomolecules 9:5190
    [Google Scholar]
  60. 60. 
    Guo X, Wang X, Wang Z, Banerjee S, Yang J et al. 2016. Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis. Nat. Cell Biol. 18:202–12
    [Google Scholar]
  61. 61. 
    VerPlank JJS, Goldberg AL. 2017. Regulating protein breakdown through proteasome phosphorylation. Biochem. J. 474:3355–71
    [Google Scholar]
  62. 62. 
    DiDonato JA, Mercurio F, Karin M 2012. NF-κB and the link between inflammation and cancer. Immunol. Rev. 246:379–400
    [Google Scholar]
  63. 63. 
    Niazi S, Purohit M, Niazi JH 2018. Role of p53 circuitry in tumorigenesis: a brief review. Eur. J. Med. Chem. 158:7–24
    [Google Scholar]
  64. 64. 
    Harashima H, Dissmeyer N, Schnittger A 2013. Cell cycle control across the eukaryotic kingdom. Trends Cell Biol 23:345–56
    [Google Scholar]
  65. 65. 
    Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL 2011. Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 11:558–72
    [Google Scholar]
  66. 66. 
    Jares P, Colomer D, Campo E 2012. Molecular pathogenesis of mantle cell lymphoma. J. Clin. Investig. 122:3416–23
    [Google Scholar]
  67. 67. 
    Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Anderson KC, Richardson PG 2017. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev 36:561–84
    [Google Scholar]
  68. 68. 
    Fricker LD. 2012. Neuropeptides and Other Bioactive Peptides: From Discovery to Function Charleston, S.C: Morgan & Claypool Publ.
    [Google Scholar]
  69. 69. 
    Becker SH, Darwin KH. 2017. Bacterial proteasomes: mechanistic and functional insights. Microbiol. Mol. Biol. Rev. 81:e00036–16
    [Google Scholar]
  70. 70. 
    Saric T, Graef CI, Goldberg AL 2004. Pathway for degradation of peptides generated by proteasomes: a key role for thimet oligopeptidase and other metallopeptidases. J. Biol. Chem. 279:46723–32
    [Google Scholar]
  71. 71. 
    Ferro ES, Rioli V, Castro LM, Fricker LD 2014. Intracellular peptides: from discovery to function. EuPA Open Proteom 3:143–51
    [Google Scholar]
  72. 72. 
    Reits E, Griekspoor A, Neijssen J, Groothuis T, Jalink K et al. 2003. Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity 18:97–108
    [Google Scholar]
  73. 73. 
    Reits E, Neijssen J, Herberts C, Benckhuijsen W, Janssen L et al. 2004. A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation. Immunity 20:495–506
    [Google Scholar]
  74. 74. 
    Grossmann ME, Madden BJ, Gao F, Pang YP, Carpenter JE et al. 2004. Proteomics shows Hsp70 does not bind peptide sequences indiscriminately in vivo. Exp. Cell Res. 297:108–17
    [Google Scholar]
  75. 75. 
    Lev A, Takeda K, Zanker D, Maynard JC, Dimberu P et al. 2008. The exception that reinforces the rule: crosspriming by cytosolic peptides that escape degradation. Immunity 28:787–98
    [Google Scholar]
  76. 76. 
    Rioli V, Gozzo FC, Heimann AS, Linardi A, Krieger JE et al. 2003. Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme. J. Biol. Chem. 278:8547–55
    [Google Scholar]
  77. 77. 
    Che FY, Lim J, Biswas R, Pan H, Fricker LD 2005. Quantitative neuropeptidomics of microwave-irradiated mouse brain and pituitary. Mol. Cell. Proteom. 4:1391–405
    [Google Scholar]
  78. 78. 
    Fricker LD, Lim J, Pan H, Che FY 2006. Peptidomics: identification and quantification of endogenous peptides in neuroendocrine tissues. Mass Spectrom. Rev. 25:327–44
    [Google Scholar]
  79. 79. 
    Sköld K, Svensson M, Norrman M, Sjögren B, Svenningsson P, Andren PE 2007. The significance of biochemical and molecular sample integrity in brain proteomics and peptidomics: stathmin 2-20 and peptides as sample quality indicators. Proteomics 7:4445–56
    [Google Scholar]
  80. 80. 
    Berti DA, Morano C, Russo LC, Castro LM, Cunha FM et al. 2009. Analysis of intracellular substrates and products of thimet oligopeptidase (EC 3.4.24.15) in human embryonic kidney 293 cells. J. Biol. Chem. 284:14105–16
    [Google Scholar]
  81. 81. 
    Fricker LD. 2010. Analysis of mouse brain peptides using mass spectrometry–based peptidomics: implications for novel functions ranging from non-classical neuropeptides to microproteins. Mol. Biosyst. 6:1355–65
    [Google Scholar]
  82. 82. 
    Romanova EV, Lee JE, Kelleher NL, Sweedler JV, Gulley JM 2010. Mass spectrometry screening reveals peptides modulated differentially in the medial prefrontal cortex of rats with disparate initial sensitivity to cocaine. AAPS J 12:443–54
    [Google Scholar]
  83. 83. 
    Gelman JS, Sironi J, Castro LM, Ferro ES, Fricker LD 2011. Peptidomic analysis of human cell lines. J. Proteome Res. 10:1583–92
    [Google Scholar]
  84. 84. 
    Van Dijck A, Hayakawa E, Landuyt B, Baggerman G, Van Dam D et al. 2011. Comparison of extraction methods for peptidomics analysis of mouse brain tissue. J. Neurosci. Meth. 197:231–37
    [Google Scholar]
  85. 85. 
    Berezniuk I, Sironi JJ, Wardman J, Pasek RC, Berbari NF et al. 2013. Quantitative peptidomics of Purkinje cell degeneration mice. PLOS ONE 8:e60981
    [Google Scholar]
  86. 86. 
    Dasgupta S, Castro LM, Dulman R, Yang C, Schmidt M et al. 2014. Proteasome inhibitors alter levels of intracellular peptides in HEK293T and SH-SY5Y cells. PLOS ONE 9:e103604
    [Google Scholar]
  87. 87. 
    Romanova EV, Rubakhin SS, Ossyra JR, Zombeck JA, Nosek MR et al. 2015. Differential peptidomics assessment of strain and age differences in mice in response to acute cocaine administration. J. Neurochem. 135:1038–48
    [Google Scholar]
  88. 88. 
    Dasgupta S, Fishman MA, Mahallati H, Castro LM, Tashima AK et al. 2015. Reduced levels of proteasome products in a mouse striatal cell model of Huntington's disease. PLOS ONE 10:e0145333
    [Google Scholar]
  89. 89. 
    Berti DA, Russo LC, Castro LM, Cruz L, Gozzo FC et al. 2012. Identification of intracellular peptides in rat adipose tissue: insights into insulin resistance. Proteomics 12:2668–81
    [Google Scholar]
  90. 90. 
    Dasgupta S, Fishman MA, Castro LM, Tashima AK, Ferro ES, Fricker LD 2019. Effect of protein denaturation and enzyme inhibitors on proteasomal-mediated production of peptides in human embryonic kidney cells. Biomolecules 9:6207
    [Google Scholar]
  91. 91. 
    Teixeira CMM, Correa CN, Iwai LK, Ferro ES, Castro LM 2019. Characterization of intracellular peptides from zebrafish (Danio rerio) brain. Zebrafish 16:240–51
    [Google Scholar]
  92. 92. 
    Dasgupta S, Yang C, Castro LM, Tashima AK, Ferro ES et al. 2016. Analysis of the yeast peptidome and comparison with the human peptidome. PLOS ONE 11:e0163312
    [Google Scholar]
  93. 93. 
    Ramachandran KV, Margolis SS. 2017. A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat. Struct. Mol. Biol. 24:419–30
    [Google Scholar]
  94. 94. 
    Ramachandran KV, Fu JM, Schaffer TB, Na CH, Delannoy M, Margolis SS 2018. Activity-dependent degradation of the nascentome by the neuronal membrane proteasome. Mol. Cell 71:169–77.e6
    [Google Scholar]
  95. 95. 
    Moorthy AK, Savinova OV, Ho JQ, Wang VY, Vu D, Ghosh G 2006. The 20S proteasome processes NF-κB1 p105 into p50 in a translation-independent manner. EMBO J 25:1945–56
    [Google Scholar]
  96. 96. 
    Wilk S, Orlowski M. 1983. Evidence that pituitary cation-sensitive neutral endopeptidase is a multicatalytic protease complex. J. Neurochem. 40:842–49
    [Google Scholar]
  97. 97. 
    Hayashi M, Inomata M, Saito Y, Ito H, Kawashima S 1991. Activation of intracellular calcium-activated neutral proteinase in erythrocytes and its inhibition by exogenously added inhibitors. Biochim. Biophys. Acta 1094:249–56
    [Google Scholar]
  98. 98. 
    Bogyo M, McMaster JS, Gaczynska M, Tortorella D, Goldberg AL, Ploegh H 1997. Covalent modification of the active site threonine of proteasomal β subunits and the Escherichia coli homolog HsIV by a new class of inhibitors. PNAS 94:6629–34
    [Google Scholar]
  99. 99. 
    Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM 1999. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. PNAS 96:10403–8
    [Google Scholar]
  100. 100. 
    Omura S, Fujimoto T, Otoguro K, Matsuzaki K, Moriguchi R et al. 1991. Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells. J. Antibiot. 44:113–16
    [Google Scholar]
  101. 101. 
    Omura S, Crump A. 2019. Lactacystin: first-in-class proteasome inhibitor still excelling and an exemplar for future antibiotic research. J. Antibiot. 72:189–201
    [Google Scholar]
  102. 102. 
    Hanada M, Sugawara K, Kaneta K, Toda S, Nishiyama Y et al. 1992. Epoxomicin, a new antitumor agent of microbial origin. J. Antibiot. 45:1746–52
    [Google Scholar]
  103. 103. 
    Teicher BA, Anderson KC. 2015. CCR 20th anniversary commentary: In the beginning, there was PS-341. Clin. Cancer Res. 21:939–41
    [Google Scholar]
  104. 104. 
    Adams J, Behnke M, Chen S, Cruickshank AA, Dick LR et al. 1998. Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg. Med. Chem. Lett. 8:333–38
    [Google Scholar]
  105. 105. 
    Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M et al. 2010. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 70:1970–80
    [Google Scholar]
  106. 106. 
    Manton CA, Johnson B, Singh M, Bailey CP, Bouchier-Hayes L, Chandra J 2016. Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo. Sci. Rep. 6:18953
    [Google Scholar]
  107. 107. 
    Di K, Lloyd GK, Abraham V, MacLaren A, Burrows FJ et al. 2016. Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier. Neuro Oncol 18:840–48
    [Google Scholar]
  108. 108. 
    Li Y, Tomko RJ Jr, Hochstrasser M 2015. Proteasomes: isolation and activity assays. Curr. Protoc. Cell Biol. 67:343.1–20
    [Google Scholar]
  109. 109. 
    Chou TF, Deshaies RJ. 2011. Quantitative cell-based protein degradation assays to identify and classify drugs that target the ubiquitin-proteasome system. J. Biol. Chem. 286:16546–54
    [Google Scholar]
  110. 110. 
    Thibaudeau TA, Smith DM. 2019. A practical review of proteasome pharmacology. Pharmacol. Rev. 71:170–97
    [Google Scholar]
  111. 111. 
    Milner E, Gutter-Kapon L, Bassani-Strenberg M, Barnea E, Beer I, Admon A 2013. The effect of proteasome inhibition on the generation of the human leukocyte antigen (HLA) peptidome. Mol. Cell Proteom. 12:1853–64
    [Google Scholar]
  112. 112. 
    Kisselev AF, Callard A, Goldberg AL 2006. Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate. J. Biol. Chem. 281:8582–90
    [Google Scholar]
  113. 113. 
    Schwartz R, Davidson T. 2004. Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncology 18:14–21
    [Google Scholar]
  114. 114. 
    Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G et al. 2011. Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother. Pharmacol. 67:57–67
    [Google Scholar]
  115. 115. 
    Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X et al. 2011. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12:431–40
    [Google Scholar]
  116. 116. 
    Shabaneh TB, Downey SL, Goddard AL, Screen M, Lucas MM et al. 2013. Molecular basis of differential sensitivity of myeloma cells to clinically relevant bolus treatment with bortezomib. PLOS ONE 8:e56132
    [Google Scholar]
  117. 117. 
    Heine S, Kleih M, Gimenez N, Bopple K, Ott G et al. 2018. Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA. J. Hematol. Oncol. 11:112
    [Google Scholar]
  118. 118. 
    Landowski TH, Megli CJ, Nullmeyer KD, Lynch RM, Dorr RT 2005. Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Cancer Res 65:3828–36
    [Google Scholar]
  119. 119. 
    Prenzel T, Begus-Nahrmann Y, Kramer F, Hennion M, Hsu C et al. 2011. Estrogen-dependent gene transcription in human breast cancer cells relies upon proteasome-dependent monoubiquitination of histone H2B. Cancer Res 71:5739–53
    [Google Scholar]
  120. 120. 
    Minsky N, Shema E, Field Y, Schuster M, Segal E, Oren M 2008. Monoubiquitinated H2B is associated with the transcribed region of highly expressed genes in human cells. Nat. Cell Biol. 10:483–88
    [Google Scholar]
  121. 121. 
    Ciechanover A. 1994. The ubiquitin-proteasome proteolytic pathway. Cell 79:13–21
    [Google Scholar]
  122. 122. 
    Kisselev AF, Akopian TN, Woo KM, Goldberg AL 1999. The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes: implications for understanding the degradative mechanism and antigen presentation. J. Biol. Chem. 274:3363–71
    [Google Scholar]
  123. 123. 
    Sillerud LO, Larson RS. 2005. Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction. Curr. Protein Pept. Sci. 6:151–69
    [Google Scholar]
  124. 124. 
    Rubinstein M, Niv MY. 2009. Peptidic modulators of protein-protein interactions: progress and challenges in computational design. Biopolymers 91:505–13
    [Google Scholar]
  125. 125. 
    Churchill EN, Qvit N, Mochly-Rosen D 2009. Rationally designed peptide regulators of protein kinase C. Trends Endocrinol. Metab. 20:25–33
    [Google Scholar]
  126. 126. 
    Arkin MR, Whitty A. 2009. The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions. Curr. Opin. Chem. Biol. 13:284–90
    [Google Scholar]
  127. 127. 
    Groner B, Weber A, Mack L 2012. Increasing the range of drug targets: interacting peptides provide leads for the development of oncoprotein inhibitors. Bioengineered 3:320–25
    [Google Scholar]
  128. 128. 
    London N, Raveh B, Schueler-Furman O 2013. Peptide docking and structure-based characterization of peptide binding: from knowledge to know-how. Curr. Opin. Struct. Biol. 23:894–902
    [Google Scholar]
  129. 129. 
    Swanson CJ, Sivaramakrishnan S. 2014. Harnessing the unique structural properties of isolated α-helices. J. Biol. Chem. 289:25460–67
    [Google Scholar]
  130. 130. 
    Ferro ES, Hyslop S, Camargo AC 2004. Intracellullar peptides as putative natural regulators of protein interactions. J. Neurochem. 91:769–77
    [Google Scholar]
  131. 131. 
    Haynes CM, Yang Y, Blais SP, Neubert TA, Ron D 2010. The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. . elegans. Mol. Cell 37:529–40
    [Google Scholar]
  132. 132. 
    Kondo T, Plaza S, Zanet J, Benrabah E, Valenti P et al. 2010. Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science 329:336–39
    [Google Scholar]
  133. 133. 
    Cunha FM, Berti DA, Ferreira ZS, Klitzke CF, Markus RP, Ferro ES 2008. Intracellular peptides as natural regulators of cell signaling. J. Biol. Chem. 283:24448–59
    [Google Scholar]
  134. 134. 
    Russo LC, Asega AF, Castro LM, Negraes PD, Cruz L et al. 2012. Natural intracellular peptides can modulate the interactions of mouse brain proteins and thimet oligopeptidase with 14-3-3 epsilon and calmodulin. Proteomics 12:2641–55
    [Google Scholar]
  135. 135. 
    de Araujo CB, Russo LC, Castro LM, Forti FL, do Monte ER et al. 2014. A novel intracellular peptide derived from G1/S cyclin D2 induces cell death. J. Biol. Chem. 289:16711–26
    [Google Scholar]
  136. 136. 
    Monte ER, Rossato C, Llanos RP, Russo LC, de Castro LM et al. 2017. Interferon-gamma activity is potentiated by an intracellular peptide derived from the human 19S ATPase regulatory subunit 4 of the proteasome. J. Proteom. 151:74–82
    [Google Scholar]
  137. 137. 
    Russo LC, Araujo CB, Iwai LK, Ferro ES, Forti FL 2017. A cyclin D2-derived peptide acts on specific cell cycle phases by activating ERK1/2 to cause the death of breast cancer cells. J. Proteom. 151:24–32
    [Google Scholar]
  138. 138. 
    Reckziegel P, Festuccia WT, Britto LRG, Jang KLL, Romao CM et al. 2017. A novel peptide that improves metabolic parameters without adverse central nervous system effects. Sci. Rep. 7:14781
    [Google Scholar]
  139. 139. 
    Li Y, Wang X, Wang F, You L, Xu P et al. 2019. Identification of intracellular peptides associated with thermogenesis in human brown adipocytes. J. Cell Physiol. 234:7104–14
    [Google Scholar]
  140. 140. 
    Im A, Hakim FT, Pavletic SZ 2017. Novel targets in the treatment of chronic graft-versus-host disease. Leukemia 31:543–54
    [Google Scholar]
  141. 141. 
    Liu H, Wan C, Ding Y, Han R, He Y et al. 2017. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production. FASEB J 31:1756–66
    [Google Scholar]
  142. 142. 
    Kraus M, Bader J, Geurink PP, Weyburne ES, Mirabella AC et al. 2015. The novel β2-selective proteasome inhibitor LU-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells. Haematologica 100:1350–60
    [Google Scholar]
  143. 143. 
    Yoshida T, Ri M, Kanamori T, Aoki S, Ashour R et al. 2018. Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits. Oncotarget 9:9975–91
    [Google Scholar]
  144. 144. 
    Lee RC, Ambros V. 2001. An extensive class of small RNAs in Caenorhabditis elegans. . Science 294:862–64
    [Google Scholar]
  145. 145. 
    Kniepert A, Groettrup M. 2014. The unique functions of tissue-specific proteasomes. Trends Biochem. Sci. 39:17–24
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010919-023603
Loading
/content/journals/10.1146/annurev-pharmtox-010919-023603
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error