Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy

BMC Medicine

Volumn 12, Issue 1, 2014, Pages

  Deshaies, Raymond J ^a  

^a California Institute of Technology HHMI   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATASE INHIBITOR; B AP 15; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; BORTEZOMIB; CARFILZOMIB; COMPOUND I; DBEQ; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IXAZOMIB; IXAZOMIB CITRATE; LIGASE INHIBITOR; ML 240; ML 241; MLN 7243; NMS 873; PROTEASOME; PROTEASOME INHIBITOR; PROTEIN P97; PYR 41; RA 190; TRANSCRIPTION FACTOR NRF1; UBIQUITIN; UBIQUITIN PROTEIN LIGASE; UNCLASSIFIED DRUG; ADENOSINE TRIPHOSPHATASE; ANTINEOPLASTIC AGENT; NUCLEAR PROTEIN; P97 ATPASE;

CANCER THERAPY; CHEMOSENSITIVITY; CLINICAL TRIAL (TOPIC); DISORDERS OF AMINO ACID AND PROTEIN METABOLISM; DRUG CLEARANCE; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG SPECIFICITY; DRUG TARGETING; ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION; ENZYME INHIBITION; ENZYME SUBSTRATE; HUMAN; MANTLE CELL LYMPHOMA CELL; MULTIPLE MYELOMA CELL LINE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN FUNCTION; PROTEIN HOMEOSTASIS; PROTEIN MISFOLDING; PROTEIN QUALITY CONTROL; PROTEIN TARGETING; PROTEOTOXIC CRISIS; REVIEW; STRUCTURE ACTIVITY RELATION; UNFOLDED PROTEIN RESPONSE; ANIMAL; METABOLISM; NEOPLASMS;

ADENOSINE TRIPHOSPHATASES; ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; NEOPLASMS; NUCLEAR PROTEINS; PROTEASOME ENDOPEPTIDASE COMPLEX; PROTEASOME INHIBITORS; UBIQUITIN; UBIQUITIN-ACTIVATING ENZYMES;

EID: 84920861391     PISSN: None     EISSN: 17417015     Source Type: Journal    
DOI: 10.1186/s12915-014-0094-0     Document Type: Review

References (123)

1. Hershko A, Ciechanover A: The ubiquitin system. Annu Rev Biochem 1998, 67:425-479.
2. Balch WE, Morimoto RI, Dillin A, Kelly JW: Adapting proteostasis for disease intervention. Science 2008, 319:916-919.
3. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW: Cancer genome landscapes. Science 2013, 339:1546-1558.
4. Weaver BA, Cleveland DW: Does aneuploidy cause cancer? Curr Opin Cell Biol 2006, 18:658-667.
5. Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA, Housman DE, Amon A: Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 2008, 322:703-709.
6. Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP, Dunham MJ, Amon A: Identification of aneuploidy-tolerating mutations. Cell 2010, 143:71-83.
7. Warner JR, Mitra G, Schwindinger WF, Studeny M, Fried HM: Saccharomyces cerevisiae coordinates accumulation of yeast ribosomal proteins by modulating mRNA splicing, translational initiation, and protein turnover. Mol Cell Biol 1985, 5:1512-1521.
8. Dephoure N, Hwang S, O'Sullivan C, Dodgson SE, Gygi SP, Amon A, Torres EM: Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. eLife 2014, 3:e03023.
9. Williams BR, Amon A: Aneuploidy: cancer's fatal flaw? Cancer Res 2009, 69:5289-5291.
10. Luo J, Solimini NL, Elledge SJ: Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009, 136:823-837.
11. Whitesell L, Lindquist SL: HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005, 5:761-772.
12. Guo JY, Xia B, White E: Autophagy-mediated tumor promotion. Cell 2013, 155:1216-1219.
13. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ, Amon A: Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 2007, 317:916-924.
14. Adams J: The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004, 4:349-360.
15. Finley D: Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem 2009, 78:477-513.
16. Berkers CR, Verdoes M, Lichtman E, Fiebiger E, Kessler BM, Anderson KC, Ploegh HL, Ovaa H, Galardy PJ: Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. Nat Methods 2005, 2:357-362.
17. Altun M, Galardy PJ, Shringarpure R, Hideshima T, LeBlanc R, Anderson KC, Ploegh HL, Kessler BM: Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. Cancer Res 2005, 65:7896-7901.
18. Kisselev AF, Callard A, Goldberg AL: Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate. J Biol Chem 2006, 281:8582-8590.
19. Matyskiela ME, Lander GC, Martin A: Conformational switching of the 26S proteasome enables substrate degradation. Nat Struct Mol Biol 2013, 20:781-788.
20. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC: Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 2005, 102:8567-8572.
21. Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, Fayad L, Dang NH, Samaniego F, Wang M, Broglio K, Samuels B, Gilles F, Sarris AH, Hart S, Trehu E, Schenkein D, Cabanillas F, Rodriguez AM: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 2005, 23:667-675.
22. O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD: Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 2005, 23:676-684.
23. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC, Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigator: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005, 352:2487-2498.
24. ClinicalTrials.gov, search term "bortezomib". [http://clinicaltrials.gov/ct2/ results?term=bortezomib&Search=Search]
25. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, Jiang J, Laidig GJ, Lewis ER, Parlati F, Shenk KD, Smyth MS, Sun CM, Vallone MK, Woo TM, Molineaux CJ, Bennett MK: Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007, 67:6383-6391.
26. Ni H, Ergin M, Huang Q, Qin JZ, Amin HM, Martinez RL, Saeed S, Barton K, Alkan S: Analysis of expression of nuclear factor kappa B (NF-kappa B) in multiple myeloma: downregulation of NF-kappa B induces apoptosis. Br J Haematol 2001, 115:279-286.
27. Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, Dave S, Hurt EM, Tan B, Zhao H, Stephens O, Santra M, Williams DR, Dang L, Barlogie B, Shaughnessy JD Jr, Kuehl WM, Staudt LM: Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007, 12:115-130.
28. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, Braggio E, Henry T, Zhu YX, Fogle H, Price-Troska T, Ahmann G, Mancini C, Brents LA, Kumar S, Greipp P, Dispenzieri A, Bryant B, Mulligan G, Bruhn L, Barrett M, Valdez R, Trent J, Stewart AK, Carpten J, Bergsagel PL: Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007, 12:131-144.
29. Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, Sougnez C, Knoechel B, Gould J, Saksena G, Cibulskis K, McKenna A, Chapman MA, Straussman R, Levy J, Perkins LM, Keats JJ, Schumacher SE, Getz G, Rosenberg M, Golub TR, Multiple Myeloma Research Consortium: Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 2014, 25:91-101.
30. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T: The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 1994, 78:773-785.
31. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC: NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002, 277:16639-16647.
32. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, Mitsiades C, Munshi NC, Richardson PG, Carrasco RD, Anderson KC: Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 2009, 114:1046-1052.
33. Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S: Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer 2008, 7:40.
34. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH: Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006, 107:4907-4916.
35. Walter P, Ron D: The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011, 334:1081-1086.
36. Smith MH, Ploegh HL, Weissman JS: Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 2011, 334:1086-1090.
37. Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, Hahn S, Schreiber S, Wilhelm S, Herrmann M, Jäck HM, Voll RE: Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 2007, 67:1783-1792.
38. Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE, Chung KC, Tiedemann RE: Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 2013, 24:289-304.
39. Weniger MA, Rizzatti EG, Pèrez-Galán P, Liu D, Wang Q, Munson PJ, Raghavachari N, White T, Tweito MM, Dunleavy K, Ye Y, Wilson WH, Wiestner A: Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. Clin Cancer Res 2011, 17:5101-5112.
40. Cenci S, Oliva L, Cerruti F, Milan E, Bianchi G, Raule M, Mezghrani A, Pasqualetto E, Sitia R, Cascio P: Pivotal Advance: protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. J Leukocyte Biol 2012, 92:921-931.
41. Shabaneh TB, Downey SL, Goddard AL, Screen M, Lucas MM, Eastman A, Kisselev AF: Molecular basis of differential sensitivity of myeloma cells to clinically relevant bolus treatment with bortezomib. PLoS One 2013, 8:e56132.
42. Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, Pien CS, Millikan RE, Tu SM, Pagliaro L, Kim J, Adams J, Elliott P, Esseltine D, Petrusich A, Dieringer P, Perez C, Logothetis CJ: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 2004, 22:2108-2121.
43. Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J: Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010, 70:1970-1980.
44. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC: Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002, 99:14374-14379.
45. Meiners S, Heyken D, Weller A, Ludwig A, Stangl K, Kloetzel PM, Kruger E: Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of Mammalian proteasomes. J Biol Chem 2003, 278:21517-21525.
46. Suzuki E, Demo S, Deu E, Keats J, Arastu-Kapur S, Bergsagel PL, Bennett MK, Kirk CJ: Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PLoS One 2011, 6:e27996.
47. Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, Sabbatini P, Miller V, Hensley ML, Pezzulli S, Canales C, Daud A, Spriggs DR: A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 2002, 8:2505-2511.
48. Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM: Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci U S A 1999, 96:10403-10408.
49. Myung J, Kim KB, Lindsten K, Dantuma NP, Crews CM: Lack of proteasome active site allostery as revealed by subunit-specific inhibitors. Mol Cell 2001, 7:411-420.
50. O'Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, Orlowski RZ: A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 2009, 15:7085-7091.
51. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S: A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012, 120:2817-2825.
52. Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R: Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood 2013, 122:3122-3128.
53. Papadopoulos KP, Burris HA III, Gordon M, Lee P, Sausville EA, Rosen PJ, Patnaik A, Cutler RE Jr, Wang Z, Lee S, Jones SF, Infante JR: A phase I/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors. Cancer Chemother Pharmacol 2013, 72:861-868.
54. ClinicalTrials.gov, search term, "carfilzomib". [http://clinicaltrials.gov/ct2/results?term=carfilzomib&recr=Open]
55. Rowinsky E: The Vinca Alkaloids. In Holland-Frei Cancer Medicine. Edited by Kuffe DW, Pollock RE, Weischselbaum RR. Hamilton (ON): BC Decker; 2003.
56. Anchoori RK, Karanam B, Peng S, Wang JW, Jiang R, Tanno T, Orlowski RZ, Matsui W, Zhao M, Rudek MA, Hung CF, Chen X, Walters KJ, Roden RB: A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer. Cancer Cell 2013, 24:791-805.
57. Tian Z, D'Arcy P, Wang X, Ray A, Tai YT, Hu Y, Carrasco RD, Richardson P, Linder S, Chauhan D, Anderson KC: A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 2014, 123:706-716.
58. Parlati F, Aujay M, Bennett MK: Substrate for Rpn11 enzymatic activity. United States: Proteolix; 2010.
59. PubChem: Summary assay for small molecule inhibitors of Rpn11 in a Fluorescent Polarization assay. [http://pubchem.ncbi.nlm.nih.gov/assay/ assay.cgi?aid=588509&loc=ea_ras]
60. Richardson PG, Hungria VTM, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa B-R, Corrado C, San-Miguel JF: Panorama 1: a randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2014, 32:8510.
61. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL: Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014, 343:301-305.
62. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr: The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014, 343:305-309.
63. Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman MF, Thakurta A, Klippel A, Handa H, Daniel TO, Schafer PH, Chopra R: Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol 2014, 164:811-821.
64. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Cullis CA: An inhibitor of NEDD8-activating enzyme as a novel approach to treat cancer. Nature 2009, 458:732-736.
65. Yang Y, Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, Pierre SA, Jensen JP, Davydov IV, Oberoi P, Li CC, Kenten JH, Beutler JA, Vousden KH, Weissman AM: Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res 2007, 67:9472-9481.
66. Chen JJ, Tsu CA, Gavin JM, Milhollen MA, Bruzzese FJ, Mallender WD, Sintchak MD, Bump NJ, Yang X, Ma J, Loke HK, Xu Q, Li P, Bence NF, Brownell JE, Dick LR: Mechanistic studies of substrate-assisted inhibition of ubiquitin-activating enzyme by adenosine sulfamate analogues. J Biol Chem 2011, 286:40867-40877.
67. ClinicalTrials.gov, search term, "MLN7243". [http://clinicaltrials.gov/ct2/ show/NCT02045095?term=mln7243&rank=1]
68. Volkmann K, Lucas JL, Vuga D, Wang X, Brumm D, Stiles C, Kriebel D, Der-Sarkissian A, Krishnan K, Schweitzer C, Liu Z, Malyankar UM, Chiovitti D, Canny M, Durocher D, Sicheri F, Patterson JB: Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease. J Biol Chem2011, 286:12743-12755.
69. Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP: The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc Natl Acad Sci U S A 2012, 109:E869-E878.
70. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC: Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 2011, 117:1311-1314.
71. Wang H, Blais J, Ron D, Cardozo T: Structural determinants of PERK inhibitor potency and selectivity. Chem Biol Drug Des 2010, 76:480-495.
72. Harding HP, Zyryanova AF, Ron D: Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK. J Biol Chem 2012, 287:44338-44344.
73. Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, Choudhry AE, Alsaid H, Jucker BM, Axten JM, Kumar R: Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 2013, 73:1993-2002.
74. Ye Y, Meyer HH, Rapoport TA: The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 2001, 414:652-656.
75. Dai RM, Chen E, Longo DL, Gorbea CM, Li CC: Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome, in ubiquitin-proteasome-mediated degradation of IkappaBalpha. J Biol Chem 1998, 273:3562-3573.
76. Li JM, Wu H, Zhang W, Blackburn MR, Jin J: The p97-UFD1L-NPL4 protein complex mediates cytokine-induced IkappaBalpha proteolysis. Mol Cell Biol 2014, 34:335-347.
77. Yamamoto S, Tomita Y, Nakamori S, Hoshida Y, Iizuka N, Okami J, Nagano H, Dono K, Umeshita K, Sakon M, Ishikawa O, Ohigashi H, Aozasa K, Monden M: Valosin-containing protein (p97) and Ki-67 expression is a useful marker in detecting malignant behavior of pancreatic endocrine neoplasms. Oncology 2004, 66:468-475.
78. Yamamoto S, Tomita Y, Hoshida Y, Iizuka N, Monden M, Yamamoto S, Iuchi K, Aozasa K: Expression level of valosin-containing protein (p97) is correlated with progression and prognosis of non-small-cell lung carcinoma. Ann Surg Oncol 2004, 11:697-704.
79. Yamamoto S, Tomita Y, Hoshida Y, Nagano H, Dono K, Umeshita K, Sakon M, Ishikawa O, Ohigashi H, Nakamori S, Monden M, Aozasa K: Increased expression of valosin-containing protein (p97) is associated with lymph node metastasis and prognosis of pancreatic ductal adenocarcinoma. Ann Surg Oncol 2004, 11:165-172.
80. Yamamoto S, Tomita Y, Hoshida Y, Takiguchi S, Fujiwara Y, Yasuda T, Yano M, Nakamori S, Sakon M, Monden M, Aozasa K: Expression level of valosin-containing protein is strongly associated with progression and prognosis of gastric carcinoma. J Clin Oncol 2003, 21:2537-2544.
81. Yamamoto S, Tomita Y, Nakamori S, Hoshida Y, Nagano H, Dono K, Umeshita K, Sakon M, Monden M, Aozasa K: Elevated expression of valosin-containing protein (p97) in hepatocellular carcinoma is correlated with increased incidence of tumor recurrence. J Clin Oncol 2003, 21:447-452.
82. Yamamoto S, Tomita Y, Uruno T, Hoshida Y, Qiu Y, Iizuka N, Nakamichi I, Miyauchi A, Aozasa K: Expression level of valosin-containing protein (p97) is associated with prognosis of esophageal carcinoma. Clin Cancer Res 2004, 10:5558-5565.
83. Yamamoto S, Tomita Y, Uruno T, Hoshida Y, Qiu Y, Iizuka N, Nakamichi I, Miyauchi A, Aozasa K: Increased expression of valosin-containing protein (p97) is correlated with disease recurrence in follicular thyroid cancer. Ann Surg Oncol 2005, 12:925-934.
84. Fessart D, Marza E, Taouji S, Delom F, Chevet E: P97/CDC-48: proteostasis control in tumor cell biology. Cancer Lett 2013, 337:26-34.
85. Verma R, McDonald H, Yates JR III, Deshaies RJ: Selective degradation of ubiquitinated Sic1 by purified 26S proteasome yields active S phase cyclin-Cdk. Mol Cell 2001, 8:439-448.
86. Franz A, Ackermann L, Hoppe T: Create and preserve: proteostasis in development and aging is governed by Cdc48/p97/VCP. Biochim Biophys Acta 1843, 2014:205-215.
87. Meyer H, Bug M, Bremer S: Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 2012, 14:117-123.
88. Carvalho P, Goder V, Rapoport TA: Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 2006, 126:361-373.
89. Verma R, Oania R, Fang R, Smith GT, Deshaies RJ: Cdc48/p97 mediates UV-dependent turnover of RNA Pol II. Mol Cell 2011, 41:82-92.
90. Beskow A, Grimberg KB, Bott LC, Salomons FA, Dantuma NP, Young P: A conserved unfoldase activity for the p97 AAA-ATPase in proteasomal degradation. J Mol Biol 2009, 394:732-746.
91. Verma R, Oania RS, Kolawa NJ, Deshaies RJ: Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. eLife 2013, 2:e00308.
92. Brandman O, Stewart-Ornstein J, Wong D, Larson A, Williams CC, Li GW, Zhou S, King D, Shen PS, Weibezahn J, Dunn JG, Rouskin S, Inada T, Frost A, Weissman JS: A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell 2012, 151:1042-1054.
93. Defenouillère Q, Yao Y, Mouaikel J, Namane A, Galopier A, Decourty L, Doyen A, Malabat C, Saveanu C, Jacquier A, Fromont-Racine M: Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products. Proc Natl Acad Sci U S A 2013, 110:5046-5051.
94. Buchan JR, Kolaitis RM, Taylor JP, Parker R: Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 2013, 153:1461-1474.
95. Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, Baloh RH, Weihl CC: Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 2009, 187:875-888.
96. Ju JS, Miller SE, Hanson PI, Weihl CC: Impaired protein aggregate handling and clearance underlie the pathogenesis of p97/VCP-associated disease. J Biol Chem 2008, 283:30289-30299.
97. Tresse E, Salomons FA, Vesa J, Bott LC, Kimonis V, Yao TP, Dantuma NP, Taylor JP: VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 2010, 6:217-227.
98. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP: HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 2007, 447:859-863.
99. Magnaghi P, D'Alessio R, Valsasina B, Avanzi N, Rizzi S, Asa D, Gasparri F, Cozzi L, Cucchi U, Orrenius C, Polucci P, Ballinari D, Perrera C, Leone A, Cervi G, Casale E, Xiao Y, Wong C, Anderson DJ, Galvani A, Donati D, O'Brien T, Jackson PK, Isacchi A: Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat Chem Biol 2013, 9:548-556.
100. Chou TF, Brown SJ, Minond D, Nordin BE, Li K, Jones AC, Chase P, Porubsky PR, Stoltz BM, Schoenen FJ, Patricelli MP, Hodder P, Rosen H, Deshaies RJ: A reversible inhibitor of the AAA ATPase p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc Natl Acad Sci U S A 2011, 108:4834-4839.
101. Acharya P, Liao M, Engel JC, Correia MA: Liver cytochrome P450 3A endoplasmic reticulum-associated degradation: a major role for the p97 AAA ATPase in cytochrome p450 3A extraction into the cytosol. J Biol Chem 2011, 286:3815-3828.
102. Piccirillo R, Goldberg AL: The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins. EMBO J 2012, 31:3334-3350.
103. Chou TF, Li K, Frankowski KJ, Schoenen FJ, Deshaies RJ: Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. Chem Med Chem 2013, 8:297-312.
104. Wang Q, Li L, Ye Y: Inhibition of p97-dependent protein degradation by Eeyarestatin I. J Biol Chem 2008, 283:7445-7454.
105. Bursavich MG, Parker DP, Willardsen JA, Gao ZH, Davis T, Ostanin K, Robinson R, Peterson A, Cimbora DM, Zhu JF, Richards B: 2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97). Bioorg Med Chem Lett 2010, 20:1677-1679.
106. Brown SJ, Chou TF, Deshaies R, Roberts E, Guerrero M, Minond D, Mercer BA, Hodder P, Rosen HR: Probe report for P97/cdc48 inhibitors. In Probe Reports from the NIH Molecular Libraries Program. 2010 [http://www.ncbi.nlm. nih.gov/books/NBK47346/]
107. Sasazawa Y, Kanagaki S, Tashiro E, Nogawa T, Muroi M, Kondoh Y, Osada H, Imoto M: Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein. ACS Chem Biol 2012, 7:892-900.
108. Yi P, Higa A, Taouji S, Bexiga MG, Marza E, Arma D, Castain C, Le Bail B, Simpson JC, Rosenbaum J, Balabaud C, Bioulac-Sage P, Blanc JF, Chevet E: Sorafenib-mediated targeting of the AAA(+) ATPase p97/VCP leads to disruption of the secretory pathway, endoplasmic reticulum stress, and hepatocellular cancer cell death. Mol Cancer Ther 2012, 11:2610-2620.
109. Ikeda HO, Sasaoka N, Koike M, Nakano N, Muraoka Y, Toda Y, Fuchigami T, Shudo T, Iwata A, Hori S, Yoshimura N, Kakizuka A: Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa. Sci Rep 2014, 4:5970.
110. Kang MJ, Wu T, Wijeratne EM, Lau EC, Mason DJ, Mesa C, Tillotson J, Zhang DD, Gunatilaka AA, La Clair JJ, Chapman E: Functional chromatography reveals three natural products that target the same protein with distinct mechanisms of action. Chembiochem 2014, 15:2125-2131.
111. Chou TF, Deshaies RJ: Quantitative cell-based protein degradation assays to identify and classify drugs that target the ubiquitin-proteasome system. J Biol Chem 2011, 286:16546-16554.
112. Johnson ES, Ma PC, Ota IM, Varshavsky A: A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem 1995, 270:17442-17456.
113. Dantuma NP, Lindsten K, Glas R, Jellne M, Masucci MG: Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells. Nat Biotechnol 2000, 18:538-543.
114. Kimbrel EA, Davis TN, Bradner JE, Kung AL: In vivo pharmacodynamic imaging of proteasome inhibition. Mol Imaging 2009, 8:140-147.
115. Polucci P, Magnaghi P, Angiolini M, Asa D, Avanzi N, Badari A, Bertrand J, Casale E, Cauteruccio S, Cirla A, Cozzi L, Galvani A, Jackson PK, Liu Y, Magnuson S, Malgesini B, Nuvoloni S, Orrenius C, Sirtori FR, Riceputi L, Rizzi S, Trucchi B, O'Brien T, Isacchi A, Donati D, D'Alessio R: Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors: synthesis and structure-activity relationships. J Med Chem 2013, 56:437-450.
116. Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ: Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell 2010, 38:17-28.
117. Steffen J, Seeger M, Koch A, Kruger E: Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell 2010, 40:147-158.
118. Radhakrishnan SK, den Besten W, Deshaies RJ: p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition. eLife 2014, 3:e01856.
119. Zhang Y, Ren Y, Li S, Hayes JD: Transcription factor Nrf1 is topologically repartitioned across membranes to enable target gene transactivation through its acidic glucose-responsive domains. PLoS One 2014, 9:e93458.
120. Sha Z, Goldberg AL: Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97. Curr Biol 2014, 24:1573-1583.
121. Wang W, Chan JY: Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function. J Biol Chem 2006, 281:19676-19687.
122. Auner HW, Moody AM, Ward TH, Kraus M, Milan E, May P, Chaidos A, Driessen C, Cenci S, Dazzi F, Rahemtulla A, Apperley JF, Karadimitris A, Dillon N: Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells. PLoS One 2013, 8:e74415.
123. ClinicalTrials.gov, search terms "CB-5083" and "cleave". [clinicaltrials.gov/ ct2/results?term = cb-5083 + AND + cleave&Search = Search]