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Hsp90 Co-chaperones as Drug Targets in Cancer: Current Perspectives

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Heat Shock Protein Inhibitors

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 19))

Abstract

Hsp90 is a molecular chaperone that regulates the function of numerous oncogenic transcription factors and signalling intermediates in the cell. Inhibition of Hsp90 is sufficient to induce the proteosomal degradation of many of these proteins, and as such, the Hsp90 chaperone has been regarded as a promising drug target. The appropriate functioning of the Hsp90 chaperone is dependent on its ATPase activity and interactions with a cohort of non-substrate accessory proteins known as co-chaperones. Co-chaperones associate with Hsp90 at all stages of the chaperone cycle and regulate a range of Hsp90 functions, including ATP hydrolysis and client protein binding and release. Given the ability of co-chaperones to organise the function of the Hsp90 molecular machine, these proteins are now regarded as potential drug targets. Herein the role of selected Hsp90 co-chaperones Hop, Cdc37, p23 and Aha1 as possible drug targets is discussed with a focus on cancer.

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References

  1. Hartson SD, Matts RL (2012) Approaches for defining the Hsp90-dependent proteome. Biochim Biophys Acta 1823(3):656–667. doi:10.1016/j.bbamcr.2011.08.013

    Article  CAS  Google Scholar 

  2. Picard D (2012) Preface to Hsp90. Biochim Biophys Acta 1823(3):605–606. doi:10.1016/j.bbamcr.2012.02.004

    Article  CAS  Google Scholar 

  3. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5(10):761–772

    Article  CAS  Google Scholar 

  4. Whitesell L, Lin NU (2012) HSP90 as a platform for the assembly of more effective cancer chemotherapy. Biochim Biophys Acta 1823(3):756–766. doi:10.1016/j.bbamcr.2011.12.006

    Article  CAS  Google Scholar 

  5. Chase G, Deng T, Fodor E, Leung BW, Mayer D, Schwemmle M, Brownlee G (2008) Hsp90 inhibitors reduce influenza virus replication in cell culture. Virology 377(2):431–439

    Article  CAS  Google Scholar 

  6. Cowen LE, Singh SD, Kohler JR, Collins C, Zaas AK, Schell WA, Aziz H, Mylonakis E, Perfect JR, Whitesell L, Lindquist S (2009) Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc Natl Acad Sci U S A 106(8):2818–2823

    Article  CAS  Google Scholar 

  7. Dickey CA, Eriksen J, Kamal A, Burrows F, Kasibhatla S, Eckman CB, Hutton M, Petrucelli L (2005) Development of a high throughput drug screening assay for the detection of changes in tau levels -- proof of concept with HSP90 inhibitors. Curr Alzheimer Res 2(2):231–238

    Article  CAS  Google Scholar 

  8. Geller R, Vignuzzi M, Andino R, Frydman J (2007) Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance. Genes Dev 21(2):195–205. doi:10.1101/gad.1505307

    Article  CAS  Google Scholar 

  9. Giannini G, Battistuzzi G (2015) Exploring in vitro and in vivo Hsp90 inhibitors activity against human protozoan parasites. Bioorg Med Chem Lett 25(3):462–465. doi:10.1016/j.bmcl.2014.12.048

    Article  CAS  Google Scholar 

  10. Luo W, Rodina A, Chiosis G (2008) Heat shock protein 90: translation from cancer to Alzheimer’s disease treatment? BMC Neurosci 9(Suppl 2):S7

    Article  CAS  Google Scholar 

  11. Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Doyu M, Sobue G (2006) Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. J Mol Med 84(8):635–646

    Article  CAS  Google Scholar 

  12. Zhang H, Burrows F (2004) Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 82(8):488–499

    Article  CAS  Google Scholar 

  13. Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO (1997) The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem 272(38):23843–23850

    Article  CAS  Google Scholar 

  14. Grenert JP, Johnson BD, Toft DO (1999) The importance of ATP binding and hydrolysis by hsp90 in formation and function of protein heterocomplexes. J Biol Chem 274(25):17525–17533

    Article  CAS  Google Scholar 

  15. Obermann WM, Sondermann H, Russo AA, Pavletich NP, Hartl FU (1998) In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J Cell Biol 143(4):901–910

    Article  CAS  Google Scholar 

  16. Panaretou B, Prodromou C, Roe SM, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1998) ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. EMBO J 17(16):4829–4836

    Article  CAS  Google Scholar 

  17. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425(6956):407–410

    Article  CAS  Google Scholar 

  18. Drysdale MJ, Brough PA, Massey A, Jensen MR, Schoepfer J (2006) Targeting Hsp90 for the treatment of cancer. Curr Opin Drug Discov Devel 9(4):483–495

    CAS  Google Scholar 

  19. Wang Y, Trepel JB, Neckers LM, Giaccone G (2010) STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs 11(12):1466–1476

    CAS  Google Scholar 

  20. Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, Quadt C, Buckler A, Cozens R, Drysdale MJ, Garcia-Echeverria C, Chene P (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10(2):R33. doi:10.1186/bcr1996

    Article  CAS  Google Scholar 

  21. Voruganti S, Lacroix JC, Rogers CN, Rogers J, Matts RL, Hartson SD (2013) The anticancer drug AUY922 generates a proteomics fingerprint that is highly conserved among structurally diverse Hsp90 inhibitors. J Proteome Res. doi:10.1021/pr400321x

    Google Scholar 

  22. Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, Atoyan R, Wang J, Samson M, Forrester J, DellaRocca S, Xu GX, Tao X, Zhai HX, Cai X, Qian C (2009) CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res 15(12):4046–4057. doi:10.1158/1078-0432.CCR-09-0152

    Article  CAS  Google Scholar 

  23. Whitesell L, Bagatell R, Falsey R (2003) The stress response: implications for the clinical development of hsp90 inhibitors. Curr Cancer Drug Targets 3(5):349–358

    Article  CAS  Google Scholar 

  24. Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R (1998) Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94(4):471–480

    Article  CAS  Google Scholar 

  25. Cox MB, Johnson JL (2011) The role of p23, Hop, immunophilins, and other co-chaperones in regulating Hsp90 function. Methods Mol Biol 787:45–66. doi:10.1007/978-1-61779-295-3_4

    Article  CAS  Google Scholar 

  26. Li J, Soroka J, Buchner J (2012) The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta 1823(3):624–635. doi:10.1016/j.bbamcr.2011.09.003

    Article  CAS  Google Scholar 

  27. Prodromou C, Panaretou B, Chohan S, Siligardi G, O’Brien R, Ladbury JE, Roe SM, Piper PW, Pearl LH (2000) The ATPase cycle of Hsp90 drives a molecular ‘clamp’ via transient dimerization of the N-terminal domains. EMBO J 19(16):4383–4392

    Article  CAS  Google Scholar 

  28. Csermely P, Schnaider T, Soti C, Prohaszka Z, Nardai G (1998) The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol Ther 79(2):129–168

    Article  CAS  Google Scholar 

  29. Blatch GL, Lassle M (1999) The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21(11):932–939

    Article  CAS  Google Scholar 

  30. Young JC, Obermann WM, Hartl FU (1998) Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90. J Biol Chem 273(29):18007–18010

    Article  CAS  Google Scholar 

  31. Lotz GP, Lin H, Harst A, Obermann WM (2003) Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase activity of the molecular chaperone. J Biol Chem 278(19):17228–17235

    Article  CAS  Google Scholar 

  32. Mayer MP, Nikolay R, Bukau B (2002) Aha, another regulator for hsp90 chaperones. Mol Cell 10(6):1255–1256

    Article  CAS  Google Scholar 

  33. Panaretou B, Siligardi G, Meyer P, Maloney A, Sullivan JK, Singh S, Millson SH, Clarke PA, Naaby-Hansen S, Stein R, Cramer R, Mollapour M, Workman P, Piper PW, Pearl LH, Prodromou C (2002) Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol Cell 10(6):1307–1318

    Article  CAS  Google Scholar 

  34. Rehn AB, Buchner J (2015) p23 and Aha1. Subcell Biochem 78:113–131. doi:10.1007/978-3-319-11731-7_6

    Article  CAS  Google Scholar 

  35. Retzlaff M, Hagn F, Mitschke L, Hessling M, Gugel F, Kessler H, Richter K, Buchner J (2010) Asymmetric activation of the hsp90 dimer by its cochaperone aha1. Mol Cell 37(3):344–354. doi:10.1016/j.molcel.2010.01.006

    Article  CAS  Google Scholar 

  36. Abbas-Terki T, Briand PA, Donze O, Picard D (2002) The Hsp90 co-chaperones Cdc37 and Sti1 interact physically and genetically. Biol Chem 383(9):1335–1342. doi:10.1515/BC.2002.152

    Article  CAS  Google Scholar 

  37. Calderwood SK (2015) Cdc37 as a co-chaperone to Hsp90. Subcell Biochem 78:103–112. doi:10.1007/978-3-319-11731-7_5

    Article  CAS  Google Scholar 

  38. Farrell A, Morgan DO (2000) Cdc37 promotes the stability of protein kinases Cdc28 and Cak1. Mol Cell Biol 20(3):749–754

    Article  CAS  Google Scholar 

  39. Siligardi G, Panaretou B, Meyer P, Singh S, Woolfson DN, Piper PW, Pearl LH, Prodromou C (2002) Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37. J Biol Chem 277(23):20151–20159

    Article  CAS  Google Scholar 

  40. Echtenkamp FJ, Zelin E, Oxelmark E, Woo JI, Andrews BJ, Garabedian M, Freeman BC (2011) Global functional map of the p23 molecular chaperone reveals an extensive cellular network. Mol Cell 43(2):229–241. doi:10.1016/j.molcel.2011.05.029

    Article  CAS  Google Scholar 

  41. Freeman BC, Felts SJ, Toft DO, Yamamoto KR (2000) The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies. Genes Dev 14(4):422–434

    CAS  Google Scholar 

  42. Morishima Y, Kanelakis KC, Murphy PJ, Lowe ER, Jenkins GJ, Osawa Y, Sunahara RK, Pratt WB (2003) The hsp90 cochaperone p23 is the limiting component of the multiprotein hsp90/hsp70-based chaperone system in vivo where it acts to stabilize the client protein: hsp90 complex. J Biol Chem 278(49):48754–48763

    Article  CAS  Google Scholar 

  43. Oxelmark E, Knoblauch R, Arnal S, Su LF, Schapira M, Garabedian MJ (2003) Genetic dissection of p23, an Hsp90 cochaperone, reveals a distinct surface involved in estrogen receptor signaling. J Biol Chem 278(38):36547–36555

    Article  CAS  Google Scholar 

  44. Weaver AJ, Sullivan WP, Felts SJ, Owen BA, Toft DO (2000) Crystal structure and activity of human p23, a heat shock protein 90 co-chaperone. J Biol Chem 275(30):23045–23052

    Article  CAS  Google Scholar 

  45. Alvira S, Cuellar J, Rohl A, Yamamoto S, Itoh H, Alfonso C, Rivas G, Buchner J, Valpuesta JM (2014) Structural characterization of the substrate transfer mechanism in Hsp70/Hsp90 folding machinery mediated by Hop. Nat Commun 5:5484. doi:10.1038/ncomms6484

    Article  Google Scholar 

  46. Baindur-Hudson S, Edkins AL, Blatch GL (2015) Hsp70/Hsp90 organising protein (hop): beyond interactions with chaperones and prion proteins. Subcell Biochem 78:69–90. doi:10.1007/978-3-319-11731-7_3

    Article  CAS  Google Scholar 

  47. Blatch GL, Lassle M, Zetter BR, Kundra V (1997) Isolation of a mouse cDNA encoding mSTI1, a stress-inducible protein containing the TPR motif. Gene 194(2):277–282

    Article  CAS  Google Scholar 

  48. Honore B, Leffers H, Madsen P, Rasmussen HH, Vandekerckhove J, Celis JE (1992) Molecular cloning and expression of a transformation-sensitive human protein containing the TPR motif and sharing identity to the stress-inducible yeast protein STI1. J Biol Chem 267(12):8485–8491

    CAS  Google Scholar 

  49. Lassle M, Blatch GL, Kundra V, Takatori T, Zetter BR (1997) Stress-inducible, murine protein mSTI1. Characterization of binding domains for heat shock proteins and in vitro phosphorylation by different kinases. J Biol Chem 272(3):1876–1884

    Article  CAS  Google Scholar 

  50. Nicolet CM, Craig EA (1989) Isolation and characterization of STI1, a stress-inducible gene from Saccharomyces cerevisiae. Mol Cell Biol 9(9):3638–3646

    Article  CAS  Google Scholar 

  51. Schmid AB, Lagleder S, Grawert MA, Rohl A, Hagn F, Wandinger SK, Cox MB, Demmer O, Richter K, Groll M, Kessler H, Buchner J (2012) The architecture of functional modules in the Hsp90 co-chaperone Sti1/Hop. EMBO J 31(6):1506–1517. doi:10.1038/emboj.2011.472

    Article  CAS  Google Scholar 

  52. Johnson JL (2012) Evolution and function of diverse Hsp90 homologs and cochaperone proteins. Biochim Biophys Acta 1823(3):607–613. doi:10.1016/j.bbamcr.2011.09.020

    Article  CAS  Google Scholar 

  53. Sanchez ER (2012) Chaperoning steroidal physiology: lessons from mouse genetic models of Hsp90 and its cochaperones. Biochim Biophys Acta 1823(3):722–729. doi:10.1016/j.bbamcr.2011.11.006

    Article  CAS  Google Scholar 

  54. Aoyagi S, Archer TK (2005) Modulating molecular chaperone Hsp90 functions through reversible acetylation. Trends Cell Biol 15(11):565–567

    Article  CAS  Google Scholar 

  55. Duval M, Le Boeuf F, Huot J, Gratton JP (2007) Src-mediated phosphorylation of Hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase. Mol Biol Cell 18(11):4659–4668

    Article  CAS  Google Scholar 

  56. Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S (2005) S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A 102(24):8525–8530

    Article  CAS  Google Scholar 

  57. Rao R, Fiskus W, Yang Y, Lee P, Joshi R, Fernandez P, Mandawat A, Atadja P, Bradner JE, Bhalla K (2008) HDAC6 inhibition enhances 17-AAG--mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood 112(5):1886–1893. doi:10.1182/blood-2008-03-143644

    Article  CAS  Google Scholar 

  58. Yang Y, Rao R, Shen J, Tang Y, Fiskus W, Nechtman J, Atadja P, Bhalla K (2008) Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion. Cancer Res 68(12):4833–4842. doi:10.1158/0008-5472.CAN-08-0644

    Article  CAS  Google Scholar 

  59. Cano LQ, Lavery DN, Sin S, Spanjaard E, Brooke GN, Tilman JD, Abroaf A, Gaughan L, Robson CN, Heer R, Mauri F, de Rooij J, Driouch K, Bevan CL (2015) The co-chaperone p23 promotes prostate cancer motility and metastasis. Mol Oncol 9(1):295–308. doi:10.1016/j.molonc.2014.08.014

    Article  CAS  Google Scholar 

  60. Smith JR, Clarke PA, de Billy E, Workman P (2009) Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors. Oncogene 28(2):157–169. doi:10.1038/onc.2008.380

    Article  CAS  Google Scholar 

  61. Willmer T, Contu L, Blatch GL, Edkins AL (2013) Knockdown of Hop downregulates RhoC expression, and decreases pseudopodia formation and migration in cancer cell lines. Cancer Lett 328(2):252–260. doi:10.1016/j.canlet.2012.09.021

    Article  CAS  Google Scholar 

  62. Kubota H, Yamamoto S, Itoh E, Abe Y, Nakamura A, Izumi Y, Okada H, Iida M, Nanjo H, Itoh H, Yamamoto Y (2010) Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma. Cell Stress Chaperones 15(6):1003–1011. doi:10.1007/s12192-010-0211-0

    Article  CAS  Google Scholar 

  63. Piper PW, Millson SH, Mollapour M, Panaretou B, Siligardi G, Pearl LH, Prodromou C (2003) Sensitivity to Hsp90-targeting drugs can arise with mutation to the Hsp90 chaperone, cochaperones and plasma membrane ATP binding cassette transporters of yeast. Eur J Biochem 270(23):4689–4695

    Article  CAS  Google Scholar 

  64. Felts SJ, Owen BA, Nguyen P, Trepel J, Donner DB, Toft DO (2000) The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem 275(5):3305–3312

    Article  CAS  Google Scholar 

  65. Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L (2001) Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem 276(5):3702–3708. doi:10.1074/jbc.M006864200

    Article  CAS  Google Scholar 

  66. Altieri DC, Stein GS, Lian JB, Languino LR (2012) TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta 1823(3):767–773. doi:10.1016/j.bbamcr.2011.08.007

    Article  CAS  Google Scholar 

  67. Marzec M, Eletto D, Argon Y (2012) GRP94: an HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta 1823(3):774–787. doi:10.1016/j.bbamcr.2011.10.013

    Article  CAS  Google Scholar 

  68. Liu B, Yang Y, Qiu Z, Staron M, Hong F, Li Y, Wu S, Li Y, Hao B, Bona R, Han D, Li Z (2010) Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat Commun 1:79

    Article  CAS  Google Scholar 

  69. Wakabayashi Y, Kobayashi M, Akashi-Takamura S, Tanimura N, Konno K, Takahashi K, Ishii T, Mizutani T, Iba H, Kouro T, Takaki S, Takatsu K, Oda Y, Ishihama Y, Saitoh S, Miyake K (2006) A protein associated with toll-like receptor 4 (PRAT4A) regulates cell surface expression of TLR4. J Immunol 177(3):1772–1779

    Article  CAS  Google Scholar 

  70. Wegele H, Wandinger SK, Schmid AB, Reinstein J, Buchner J (2006) Substrate transfer from the chaperone Hsp70 to Hsp90. J Mol Biol 356(3):802–811

    Article  CAS  Google Scholar 

  71. Chang HC, Nathan DF, Lindquist S (1997) In vivo analysis of the Hsp90 cochaperone Sti1 (p60). Mol Cell Biol 17(1):318–325

    Article  CAS  Google Scholar 

  72. Beraldo FH, Soares IN, Goncalves DF, Fan J, Thomas AA, Santos TG, Mohammad AH, Roffe M, Calder MD, Nikolova S, Hajj GN, Guimaraes AL, Massensini AR, Welch I, Betts DH, Gros R, Drangova M, Watson AJ, Bartha R, Prado VF, Martins VR, Prado MA (2013) Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein. FASEB J. doi:10.1096/fj.13-232280

    Google Scholar 

  73. Brinker A, Scheufler C, Von Der Mulbe F, Fleckenstein B, Herrmann C, Jung G, Moarefi I, Hartl FU (2002) Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70 x Hop x Hsp90 complexes. J Biol Chem 277(22):19265–19275

    Article  CAS  Google Scholar 

  74. Odunuga OO, Hornby JA, Bies C, Zimmermann R, Pugh DJ, Blatch GL (2003) Tetratricopeptide repeat motif-mediated Hsc70-mSTI1 interaction. Molecular characterization of the critical contacts for successful binding and specificity. J Biol Chem 278(9):6896–6904. doi:10.1074/jbc.M206867200

    Article  CAS  Google Scholar 

  75. Scheufler C, Brinker A, Bourenkov G, Pegoraro S, Moroder L, Bartunik H, Hartl FU, Moarefi I (2000) Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101(2):199–210

    Article  CAS  Google Scholar 

  76. Lee CT, Graf C, Mayer FJ, Richter SM, Mayer MP (2012) Dynamics of the regulation of Hsp90 by the co-chaperone Sti1. EMBO J 31(6):1518–1528. doi:10.1038/emboj.2012.37

    Article  CAS  Google Scholar 

  77. Onuoha SC, Coulstock ET, Grossmann JG, Jackson SE (2008) Structural studies on the co-chaperone Hop and its complexes with Hsp90. J Mol Biol 379(4):732–744

    Article  CAS  Google Scholar 

  78. Wegele H, Muller L, Buchner J (2004) Hsp70 and Hsp90 – a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1–44

    CAS  Google Scholar 

  79. Prodromou C, Siligardi G, O’Brien R, Woolfson DN, Regan L, Panaretou B, Ladbury JE, Piper PW, Pearl LH (1999) Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO J 18(3):754–762

    Article  CAS  Google Scholar 

  80. Siligardi G, Hu B, Panaretou B, Piper PW, Pearl LH, Prodromou C (2004) Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle. J Biol Chem 279(50):51989–51998

    Article  CAS  Google Scholar 

  81. Yamamoto S, Subedi GP, Hanashima S, Satoh T, Otaka M, Wakui H, Sawada K, Yokota S, Yamaguchi Y, Kubota H, Itoh H (2014) ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP). J Biol Chem 289(14):9880–9886. doi:10.1074/jbc.M114.553255

    Article  CAS  Google Scholar 

  82. Li J, Sun X, Wang Z, Chen L, Li D, Zhou J, Liu M (2012) Regulation of vascular endothelial cell polarization and migration by Hsp70/Hsp90-organizing protein. PLoS One 7(4), e36389. doi:10.1371/journal.pone.0036389

    Article  CAS  Google Scholar 

  83. Walsh N, O’Donovan N, Kennedy S, Henry M, Meleady P, Clynes M, Dowling P (2009) Identification of pancreatic cancer invasion-related proteins by proteomic analysis. Proteome Sci 7:3

    Article  CAS  Google Scholar 

  84. Sun W, Xing B, Sun Y, Du X, Lu M, Hao C, Lu Z, Mi W, Wu S, Wei H, Gao X, Zhu Y, Jiang Y, Qian X, He F (2007) Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics 6(10):1798–1808. doi:10.1074/mcp.M600449-MCP200

    Article  CAS  Google Scholar 

  85. Longshaw VM, Baxter M, Prewitz M, Blatch GL (2009) Knockdown of the co-chaperone Hop promotes extranuclear accumulation of Stat3 in mouse embryonic stem cells. Eur J Cell Biol 88(3):153–166. doi:10.1016/j.ejcb.2008.09.003

    Article  CAS  Google Scholar 

  86. Walsh N, Larkin A, Swan N, Conlon K, Dowling P, McDermott R, Clynes M (2011) RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. Cancer Lett 306(2):180–189. doi:10.1016/j.canlet.2011.03.004

    Article  CAS  Google Scholar 

  87. Ardi VC, Alexander LD, Johnson VA, McAlpine SR (2011) Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins. ACS Chem Biol 6(12):1357–1366. doi:10.1021/cb200203m

    Article  CAS  Google Scholar 

  88. Horibe T, Kawamoto M, Kohno M, Kawakami K (2012) Cytotoxic activity to acute myeloid leukemia cells by Antp-TPR hybrid peptide targeting Hsp90. J Biosci Bioeng 114(1):96–103. doi:10.1016/j.jbiosc.2012.02.016

    Article  CAS  Google Scholar 

  89. Horibe T, Kohno M, Haramoto M, Ohara K, Kawakami K (2011) Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent. J Transl Med 9:8. doi:10.1186/1479-5876-9-8

    Article  CAS  Google Scholar 

  90. Horibe T, Torisawa A, Kohno M, Kawakami K (2012) Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells. Mol Cancer 11:59. doi:10.1186/1476-4598-11-59

    Article  CAS  Google Scholar 

  91. Pimienta G, Herbert KM, Regan L (2011) A compound that inhibits the HOP-Hsp90 complex formation and has unique killing effects in breast cancer cell lines. Mol Pharm 8(6):2252–2261. doi:10.1021/mp200346y

    Article  CAS  Google Scholar 

  92. Kunicki JB, Petersen MN, Alexander LD, Ardi VC, McConnell JR, McAlpine SR (2011) Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90. Bioorg Med Chem Lett 21(16):4716–4719. doi:10.1016/j.bmcl.2011.06.083

    Article  CAS  Google Scholar 

  93. Vasko RC, Rodriguez RA, Cunningham CN, Ardi VC, Agard DA, McAlpine SR (2010) Mechanistic studies of Sansalvamide A-amide: an allosteric modulator of Hsp90. ACS Med Chem Lett 1(1):4–8. doi:10.1021/ml900003t

    Article  CAS  Google Scholar 

  94. Yi F, Regan L (2008) A novel class of small molecule inhibitors of Hsp90. ACS Chem Biol 3(10):645–654

    Article  CAS  Google Scholar 

  95. Sellers RP, Alexander LD, Johnson VA, Lin CC, Savage J, Corral R, Moss J, Slugocki TS, Singh EK, Davis MR, Ravula S, Spicer JE, Oelrich JL, Thornquist A, Pan CM, McAlpine SR (2010) Design and synthesis of Hsp90 inhibitors: exploring the SAR of Sansalvamide A derivatives. Bioorg Med Chem 18(18):6822–6856. doi:10.1016/j.bmc.2010.07.042

    Article  CAS  Google Scholar 

  96. Kimura Y, Rutherford SL, Miyata Y, Yahara I, Freeman BC, Yue L, Morimoto RI, Lindquist S (1997) Cdc37 is a molecular chaperone with specific functions in signal transduction. Genes Dev 11(14):1775–1785

    Article  CAS  Google Scholar 

  97. Lee P, Shabbir A, Cardozo C, Caplan AJ (2004) Sti1 and Cdc37 can stabilize Hsp90 in chaperone complexes with a protein kinase. Mol Biol Cell 15(4):1785–1792. doi:10.1091/mbc.E03-07-0480

    Article  CAS  Google Scholar 

  98. MacLean M, Picard D (2003) Cdc37 goes beyond Hsp90 and kinases. Cell Stress Chaperones 8(2):114–119

    Article  CAS  Google Scholar 

  99. Prince T, Sun L, Matts RL (2005) Cdk2: a genuine protein kinase client of Hsp90 and Cdc37. Biochemistry 44(46):15287–15295. doi:10.1021/bi051423m

    Article  CAS  Google Scholar 

  100. Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH (2004) The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell 116(1):87–98

    Article  CAS  Google Scholar 

  101. Zhang W, Hirshberg M, McLaughlin SH, Lazar GA, Grossmann JG, Nielsen PR, Sobott F, Robinson CV, Jackson SE, Laue ED (2004) Biochemical and structural studies of the interaction of Cdc37 with Hsp90. J Mol Biol 340(4):891–907. doi:10.1016/j.jmb.2004.05.007

    Article  CAS  Google Scholar 

  102. Eckl JM, Rutz DA, Haslbeck V, Zierer BK, Reinstein J, Richter K (2013) Cdc37 (cell division cycle 37) restricts Hsp90 (heat shock protein 90) motility by interaction with N-terminal and middle domain binding sites. J Biol Chem 288(22):16032–16042. doi:10.1074/jbc.M112.439257

    Article  CAS  Google Scholar 

  103. Vaughan CK, Gohlke U, Sobott F, Good VM, Ali MM, Prodromou C, Robinson CV, Saibil HR, Pearl LH (2006) Structure of an Hsp90-Cdc37-Cdk4 complex. Mol Cell 23(5):697–707. doi:10.1016/j.molcel.2006.07.016

    Article  CAS  Google Scholar 

  104. Lee P, Rao J, Fliss A, Yang E, Garrett S, Caplan AJ (2002) The Cdc37 protein kinase-binding domain is sufficient for protein kinase activity and cell viability. J Cell Biol 159(6):1051–1059. doi:10.1083/jcb.200210121

    Article  CAS  Google Scholar 

  105. Mandal AK, Lee P, Chen JA, Nillegoda N, Heller A, DiStasio S, Oen H, Victor J, Nair DM, Brodsky JL, Caplan AJ (2007) Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. J Cell Biol 176(3):319–328. doi:10.1083/jcb.200604106

    Article  CAS  Google Scholar 

  106. Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI, Lindquist S (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150(5):987–1001. doi:10.1016/j.cell.2012.06.047

    Article  CAS  Google Scholar 

  107. Smith JR, Workman P (2009) Targeting CDC37: an alternative, kinase-directed strategy for disruption of oncogenic chaperoning. Cell Cycle 8(3):362–372

    Article  CAS  Google Scholar 

  108. Kancha RK, Bartosch N, Duyster J (2013) Analysis of conformational determinants underlying HSP90-kinase interaction. PLoS One 8(7), e68394. doi:10.1371/journal.pone.0068394

    Article  CAS  Google Scholar 

  109. Terasawa K, Yoshimatsu K, Iemura S, Natsume T, Tanaka K, Minami Y (2006) Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases. Mol Cell Biol 26(9):3378–3389. doi:10.1128/MCB.26.9.3378-3389.2006

    Article  CAS  Google Scholar 

  110. Pascale RM, Simile MM, Calvisi DF, Frau M, Muroni MR, Seddaiu MA, Daino L, Muntoni MD, De Miglio MR, Thorgeirsson SS, Feo F (2005) Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer. Hepatology 42(6):1310–1319. doi:10.1002/hep.20962

    Article  CAS  Google Scholar 

  111. Pearl LH (2005) Hsp90 and Cdc37 – a chaperone cancer conspiracy. Curr Opin Genet Dev 15(1):55–61. doi:10.1016/j.gde.2004.12.011

    Article  CAS  Google Scholar 

  112. Schwarze SR, Fu VX, Jarrard DF (2003) Cdc37 enhances proliferation and is necessary for normal human prostate epithelial cell survival. Cancer Res 63(15):4614–4619

    CAS  Google Scholar 

  113. Stepanova L, Finegold M, DeMayo F, Schmidt EV, Harper JW (2000) The oncoprotein kinase chaperone CDC37 functions as an oncogene in mice and collaborates with both c-myc and cyclin D1 in transformation of multiple tissues. Mol Cell Biol 20(12):4462–4473. doi:10.1128/Mcb.20.12.4462-4473.2000

    Article  CAS  Google Scholar 

  114. Zhang H, Wu W, Du Y, Santos SJ, Conrad SE, Watson JT, Grammatikakis N, Gallo KA (2004) Hsp90/p50cdc37 is required for mixed-lineage kinase (MLK) 3 signaling. J Biol Chem 279(19):19457–19463

    Article  CAS  Google Scholar 

  115. Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N (2002) Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem 277(42):39858–39866. doi:10.1074/jbc.M206322200

    Article  CAS  Google Scholar 

  116. Dey B, Lightbody JJ, Boschelli F (1996) CDC37 is required for p60v-src activity in yeast. Mol Biol Cell 7(9):1405–1417

    Article  CAS  Google Scholar 

  117. Kim H, Abd Elmageed ZY, Davis C, El-Bahrawy AH, Naura AS, Ekaidi I, Abdel-Mageed AB, Boulares AH (2014) Correlation between PDZK1, Cdc37, Akt and breast cancer malignancy: the role of PDZK1 in cell growth through Akt stabilization by increasing and interacting with Cdc37. Mol Med 20:270–279. doi:10.2119/molmed.2013.00166

    Article  CAS  Google Scholar 

  118. Marino-Enriquez A, Ou WB, Cowley G, Luo B, Jonker AH, Mayeda M, Okamoto M, Eilers G, Czaplinski JT, Sicinska E, Wang Y, Taguchi T, Demetri GD, Root DE, Fletcher JA (2014) Genome-wide functional screening identifies CDC37 as a crucial HSP90-cofactor for KIT oncogenic expression in gastrointestinal stromal tumors. Oncogene 33(14):1872–1876. doi:10.1038/onc.2013.127

    Article  CAS  Google Scholar 

  119. Stepanova L, Leng X, Parker SB, Harper JW (1996) Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev 10(12):1491–1502

    Article  CAS  Google Scholar 

  120. Grammatikakis N, Lin JH, Grammatikakis A, Tsichlis PN, Cochran BH (1999) p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. Mol Cell Biol 19(3):1661–1672

    Article  CAS  Google Scholar 

  121. Stepanova L, Yang G, DeMayo F, Wheeler TM, Finegold M, Thompson TC, Harper JW (2000) Induction of human Cdc37 in prostate cancer correlates with the ability of targeted Cdc37 expression to promote prostatic hyperplasia. Oncogene 19(18):2186–2193. doi:10.1038/sj.onc.1203561

    Article  CAS  Google Scholar 

  122. Katayama Y, Sakai A, Okikawa Y, Oue N, Asaoku H, Sasaki A, Imanaka F, Tsujimoto T, Takimoto Y, Masuda R, Nakaju N, Otsuki T, Yasui W, Kimura A (2004) Cyclin D1 overexpression is not a specific grouping marker, but may collaborate with CDC37 in myeloma cells. Int J Oncol 25(3):579–595

    CAS  Google Scholar 

  123. Gray PJ, Stevenson MA, Calderwood SK (2007) Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells. Cancer Res 67(24):11942–11950. doi:10.1158/0008-5472.Cani-07-3162

    Article  CAS  Google Scholar 

  124. Wang Z, Wei W, Sun CK, Chua MS, So S (2015) Suppressing the CDC37 cochaperone in hepatocellular carcinoma cells inhibits cell cycle progression and cell growth. Liver Int 35(4):1403–1415. doi:10.1111/liv.12651

    Article  CAS  Google Scholar 

  125. Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J (1997) Interaction between Cdc37 and Cdk4 in human cells. Oncogene 14(16):1999–2004. doi:10.1038/sj.onc.1201036

    Article  CAS  Google Scholar 

  126. Zhao Q, Boschelli F, Caplan AJ, Arndt KT (2004) Identification of a conserved sequence motif that promotes Cdc37 and cyclin D1 binding to Cdk4. J Biol Chem 279(13):12560–12564. doi:10.1074/jbc.M308242200

    Article  CAS  Google Scholar 

  127. Wu P, Nielsen TE, Clausen MH (2015) FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci 36(7):422–439. doi:10.1016/j.tips.2015.04.005

    Article  CAS  Google Scholar 

  128. Cutforth T, Rubin GM (1994) Mutations in Hsp83 and cdc37 impair signaling by the sevenless receptor tyrosine kinase in Drosophila. Cell 77(7):1027–1036

    Article  CAS  Google Scholar 

  129. Gould CM, Kannan N, Taylor SS, Newton AC (2009) The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase C through a conserved PXXP motif in the C-terminal tail. J Biol Chem 284(8):4921–4935. doi:10.1074/jbc.M808436200

    Article  CAS  Google Scholar 

  130. Tatebe H, Shiozaki K (2003) Identification of Cdc37 as a novel regulator of the stress-responsive mitogen-activated protein kinase. Mol Cell Biol 23(15):5132–5142

    Article  CAS  Google Scholar 

  131. Polier S, Samant RS, Clarke PA, Workman P, Prodromou C, Pearl LH (2013) ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nat Chem Biol 9(5):307–312. doi:10.1038/nchembio.1212

    Article  CAS  Google Scholar 

  132. Zhang T, Hamza A, Cao X, Wang B, Yu S, Zhan CG, Sun D (2008) A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther 7(1):162–170. doi:10.1158/1535-7163.MCT-07-0484

    Article  CAS  Google Scholar 

  133. Zhang T, Li Y, Yu Y, Zou P, Jiang Y, Sun D (2009) Characterization of celastrol to inhibit hsp90 and cdc37 interaction. J Biol Chem 284(51):35381–35389. doi:10.1074/jbc.M109.051532

    Article  CAS  Google Scholar 

  134. Klaic L, Morimoto RI, Silverman RB (2012) Celastrol analogues as inducers of the heat shock response. Design and synthesis of affinity probes for the identification of protein targets. ACS Chem Biol 7(5):928–937. doi:10.1021/cb200539u

    Article  CAS  Google Scholar 

  135. Smith JR, de Billy E, Hobbs S, Powers M, Prodromou C, Pearl L, Clarke PA, Workman P (2015) Restricting direct interaction of CDC37 with HSP90 does not compromise chaperoning of client proteins. Oncogene 34(1):15–26. doi:10.1038/onc.2013.519

    Article  CAS  Google Scholar 

  136. Armstrong H, Wolmarans A, Mercier R, Mai B, LaPointe P (2012) The co-chaperone Hch1 regulates Hsp90 function differently than its homologue Aha1 and confers sensitivity to yeast to the Hsp90 inhibitor NVP-AUY922. PLoS One 7(11), e49322. doi:10.1371/journal.pone.0049322

    Article  CAS  Google Scholar 

  137. Meyer P, Prodromou C, Liao C, Hu B, Mark Roe S, Vaughan CK, Vlasic I, Panaretou B, Piper PW, Pearl LH (2004) Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. EMBO J 23(3):511–519

    Article  CAS  Google Scholar 

  138. Meyer P, Prodromou C, Hu B, Vaughan C, Roe SM, Panaretou B, Piper PW, Pearl LH (2003) Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions. Mol Cell 11(3):647–658

    Article  CAS  Google Scholar 

  139. Soti C, Vermes A, Haystead TA, Csermely P (2003) Comparative analysis of the ATP-binding sites of Hsp90 by nucleotide affinity cleavage: a distinct nucleotide specificity of the C-terminal ATP-binding site. Eur J Biochem 270(11):2421–2428

    Article  CAS  Google Scholar 

  140. Martinez-Yamout MA, Venkitakrishnan RP, Preece NE, Kroon G, Wright PE, Dyson HJ (2006) Localization of sites of interaction between p23 and Hsp90 in solution. J Biol Chem 281(20):14457–14464

    Article  CAS  Google Scholar 

  141. Meyer P, Prodromou C, Liao C, Hu B, Roe SM, Vaughan CK, Vlasic I, Panaretou B, Piper PW, Pearl LH (2004) Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. EMBO J 23(6):1402–1410

    Article  CAS  Google Scholar 

  142. Sun L, Prince T, Manjarrez JR, Scroggins BT, Matts RL (2012) Characterization of the interaction of Aha1 with components of the Hsp90 chaperone machine and client proteins. Biochim Biophys Acta 1823(6):1092–1101. doi:10.1016/j.bbamcr.2012.03.014

    Article  CAS  Google Scholar 

  143. Harst A, Lin H, Obermann WM (2005) Aha1 competes with Hop, p50 and p23 for binding to the molecular chaperone Hsp90 and contributes to kinase and hormone receptor activation. Biochem J 387(Pt 3):789–796. doi:10.1042/BJ20041283

    Article  CAS  Google Scholar 

  144. Holmes JL, Sharp SY, Hobbs S, Workman P (2008) Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res 68(4):1188–1197. doi:10.1158/0008-5472.can-07-3268

    Article  CAS  Google Scholar 

  145. Dunn DM, Woodford MR, Truman AW, Jensen SM, Schulman J, Caza T, Remillard TC, Loiselle D, Wolfgeher D, Blagg BS, Franco L, Haystead TA, Daturpalli S, Mayer MP, Trepel JB, Morgan RM, Prodromou C, Kron SJ, Panaretou B, Stetler-Stevenson WG, Landas SK, Neckers L, Bratslavsky G, Bourboulia D, Mollapour M (2015) c-Abl mediated tyrosine phosphorylation of Aha1 activates its co-chaperone function in cancer cells. Cell Rep 12(6):1006–1018. doi:10.1016/j.celrep.2015.07.004

    Article  CAS  Google Scholar 

  146. Afar DE, Goga A, Cohen L, Sawyers CL, McLaughlin J, Mohr RN, Witte ON (1994) Genetic approaches to defining signaling by the CML-associated tyrosine kinase BCR-ABL. Cold Spring Harb Symp Quant Biol 59:589–594

    Article  CAS  Google Scholar 

  147. Mauro MJ, Druker BJ (2001) STI571: targeting BCR-ABL as therapy for CML. Oncologist 6(3):233–238

    Article  CAS  Google Scholar 

  148. Radujkovic A, Schad M, Topaly J, Veldwijk MR, Laufs S, Schultheis BS, Jauch A, Melo JV, Fruehauf S, Zeller WJ (2005) Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL--Inhibition of P-glycoprotein function by 17-AAG. Leukemia 19(7):1198–1206. doi:10.1038/sj.leu.2403764

    Article  CAS  Google Scholar 

  149. Hildenbrand ZL, Molugu SK, Paul A, Avila GA, Herrera N, Xiao C, Cox MB, Bernal RA (2010) High-yield expression and purification of the Hsp90-associated p23, FKBP52, HOP and SGTalpha proteins. J Chromatogr B Analyt Technol Biomed Life Sci 878(28):2760–2764. doi:10.1016/j.jchromb.2010.08.016

    Article  CAS  Google Scholar 

  150. Freeman BC, Yamamoto KR (2002) Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296(5576):2232–2235. doi:10.1126/science.1073051

    Article  CAS  Google Scholar 

  151. Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH (2006) Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440(7087):1013–1017

    Article  CAS  Google Scholar 

  152. Johnson JL, Toft DO (1995) Binding of p23 and hsp90 during assembly with the progesterone receptor. Mol Endocrinol 9(6):670–678

    CAS  Google Scholar 

  153. Karagoz GE, Duarte AM, Ippel H, Uetrecht C, Sinnige T, van Rosmalen M, Hausmann J, Heck AJ, Boelens R, Rudiger SG (2011) N-terminal domain of human Hsp90 triggers binding to the cochaperone p23. Proc Natl Acad Sci U S A 108(2):580–585. doi:10.1073/pnas.1011867108

    Article  CAS  Google Scholar 

  154. McLaughlin SH, Sobott F, Yao ZP, Zhang W, Nielsen PR, Grossmann JG, Laue ED, Robinson CV, Jackson SE (2006) The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins. J Mol Biol 356(3):746–758

    Article  CAS  Google Scholar 

  155. Young JC, Hartl FU (2000) Polypeptide release by Hsp90 involves ATP hydrolysis and is enhanced by the co-chaperone p23. EMBO J 19(21):5930–5940

    Article  CAS  Google Scholar 

  156. Marcu MG, Schulte TW, Neckers L (2000) Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. J Natl Cancer Inst 92(3):242–248

    Article  CAS  Google Scholar 

  157. Bohen SP (1998) Genetic and biochemical analysis of p23 and ansamycin antibiotics in the function of Hsp90-dependent signaling proteins. Mol Cell Biol 18(6):3330–3339

    Article  CAS  Google Scholar 

  158. Grad I, McKee TA, Ludwig SM, Hoyle GW, Ruiz P, Wurst W, Floss T, Miller CA 3rd, Picard D (2006) The Hsp90 cochaperone p23 is essential for perinatal survival. Mol Cell Biol 26(23):8976–8983

    Article  CAS  Google Scholar 

  159. Forafonov F, Toogun OA, Grad I, Suslova E, Freeman BC, Picard D (2008) p23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity. Mol Cell Biol 28(10):3446–3456

    Article  CAS  Google Scholar 

  160. Fliss AE, Benzeno S, Rao J, Caplan AJ (2000) Control of estrogen receptor ligand binding by Hsp90. J Steroid Biochem Mol Biol 72(5):223–230

    Article  CAS  Google Scholar 

  161. Knoblauch R, Garabedian MJ (1999) Role for Hsp90-associated cochaperone p23 in estrogen receptor signal transduction. Mol Cell Biol 19(5):3748–3759

    Article  CAS  Google Scholar 

  162. Reebye V, Querol Cano L, Lavery DN, Brooke GN, Powell SM, Chotai D, Walker MM, Whitaker HC, Wait R, Hurst HC, Bevan CL (2012) Role of the HSP90-associated cochaperone p23 in enhancing activity of the androgen receptor and significance for prostate cancer. Mol Endocrinol 26(10):1694–1706. doi:10.1210/me.2012-1056

    Article  CAS  Google Scholar 

  163. Simpson NE, Lambert WM, Watkins R, Giashuddin S, Huang SJ, Oxelmark E, Arju R, Hochman T, Goldberg JD, Schneider RJ, Reiz LF, Soares FA, Logan SK, Garabedian MJ (2010) High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance. Cancer Res 70(21):8446–8456. doi:10.1158/0008-5472.CAN-10-1590

    Article  CAS  Google Scholar 

  164. Oxelmark E, Roth JM, Brooks PC, Braunstein SE, Schneider RJ, Garabedian MJ (2006) The cochaperone p23 differentially regulates estrogen receptor target genes and promotes tumor cell adhesion and invasion. Mol Cell Biol 26(14):5205–5213. doi:10.1128/MCB.00009-06

    Article  CAS  Google Scholar 

  165. Chadli A, Felts SJ, Wang Q, Sullivan WP, Botuyan MV, Fauq A, Ramirez-Alvarado M, Mer G (2010) Celastrol inhibits Hsp90 chaperoning of steroid receptors by inducing fibrillization of the Co-chaperone p23. J Biol Chem 285(6):4224–4231. doi:10.1074/jbc.M109.081018

    Article  CAS  Google Scholar 

  166. Hall JA, Seedarala S, Rice N, Kopel L, Halaweish F, Blagg BS (2015) Cucurbitacin D is a disruptor of the HSP90 chaperone machinery. J Nat Prod 78(4):873–879. doi:10.1021/acs.jnatprod.5b00054

    Article  CAS  Google Scholar 

  167. Ishii T, Kira N, Yoshida T, Narahara H (2013) Cucurbitacin D induces growth inhibition, cell cycle arrest, and apoptosis in human endometrial and ovarian cancer cells. Tumour Biol 34(1):285–291. doi:10.1007/s13277-012-0549-2

    Article  CAS  Google Scholar 

  168. Ku JM, Kim SR, Hong SH, Choi HS, Seo HS, Shin YC, Ko SG (2015) Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-kappaB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells. Mol Cell Biochem 409(1–2):33–43. doi:10.1007/s11010-015-2509-9

    Article  CAS  Google Scholar 

  169. Brandt GE, Schmidt MD, Prisinzano TE, Blagg BS (2008) Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships. J Med Chem 51(20):6495–6502. doi:10.1021/jm8007486

    Article  CAS  Google Scholar 

  170. Kamath SG, Chen N, Xiong Y, Wenham R, Apte S, Humphrey M, Cragun J, Lancaster JM (2009) Gedunin, a novel natural substance, inhibits ovarian cancer cell proliferation. Int J Gynecol Cancer 19(9):1564–1569. doi:10.1111/IGC.0b013e3181a83135

    Article  Google Scholar 

  171. Uddin SJ, Nahar L, Shilpi JA, Shoeb M, Borkowski T, Gibbons S, Middleton M, Byres M, Sarker SD (2007) Gedunin, a limonoid from Xylocarpus granatum, inhibits the growth of CaCo-2 colon cancer cell line in vitro. Phytother Res 21(8):757–761. doi:10.1002/ptr.2159

    Article  CAS  Google Scholar 

  172. Patwardhan CA, Fauq A, Peterson LB, Miller C, Blagg BS, Chadli A (2013) Gedunin inactivates the co-chaperone p23 protein causing cancer cell death by apoptosis. J Biol Chem 288(10):7313–7325. doi:10.1074/jbc.M112.427328

    Article  CAS  Google Scholar 

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Acknowledgments

This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.

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  1. Biomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Artillery Road, Grahamstown, 6140, South Africa

    Adrienne L. Edkins

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  1. School of Chemistry, University of New South Wales, Sidney, New South Wales, Australia

    Shelli R. McAlpine

  2. Biomedical Biotechnology Research Unit (BioBRU); Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa

    Adrienne Lesley Edkins

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Edkins, A.L. (2016). Hsp90 Co-chaperones as Drug Targets in Cancer: Current Perspectives. In: McAlpine, S., Edkins, A. (eds) Heat Shock Protein Inhibitors. Topics in Medicinal Chemistry, vol 19. Springer, Cham. https://doi.org/10.1007/7355_2015_99

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