Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90) and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents. 1. Introduction Chaperones/HSPs. Molecular chaperones are a diverse group of proteins involved in the maintenance of other “client” proteins in folded and active conformations in all cellular organisms [1–5]. The term molecular chaperone is however generally reserved for proteins with a dedicated role in protein folding and refolding derived from the HSPA (HSP70), HSPB (small HSP), HSPD (Hsp60), HSPC (Hsp90), and HSPH (large HSP) gene families originally discovered as heat shock protein (HSP) genes [2, 6]. Products of these genes direct the folding of much of the proteome, resulting in the formation of proteins or protein complexes capable of metabolic functions in the cell. A subset of these proteins is also expressed at high levels in cells after proteotoxic stresses such as exposure to heat shock, heavy metals, alcohols and sodium arsenite [7–10]. Hence, they came to be known as heat shock proteins [7, 10]. Proteotoxic stresses lead to abundant levels of unfolded, aggregated, and ubiquibinated proteins, and cells respond to such an insult by abundant synthesis of HSPs capable of resolving these perturbations to the proteome [11]. These proteins are known to increase cell survival after stress both through direct chaperoning of malfolded proteins as well as inhibition of programmed cell
References
[1]
S. Lindquist and E. A. Craig, “The heat-shock proteins,” Annual Review of Genetics, vol. 22, pp. 631–677, 1988.
[2]
R. J. Ellis, “Protein misassembly: macromolecular crowding and molecular chaperones,” Advances in Experimental Medicine and Biology, vol. 594, pp. 1–13, 2007.
[3]
M. P. Mayer and B. Bukau, “Hsp70 chaperones: cellular functions and molecular mechanism,” Cellular and Molecular Life Sciences, vol. 62, no. 6, pp. 670–684, 2005.
[4]
E. Guisbert, C. Herman, C. Z. Lu, and C. A. Gross, “A chaperone network controls the heat shock response in E. coli,” Genes and Development, vol. 18, no. 22, pp. 2812–2821, 2004.
[5]
K. Liberek, D. Skowyra, M. Zylicz, C. Johnson, and C. Georgopoulos, “The Escherichia coli DnaK chaperone, the 70-kDa heat shock protein eukaryotic equivalent, changes conformation upon ATP hydrolysis, thus triggering its dissociation from a bound target protein,” The Journal of Biological Chemistry, vol. 266, no. 22, pp. 14491–14496, 1991.
[6]
H. H. Kampinga, J. Hageman, M. J. Vos et al., “Guidelines for the nomenclature of the human heat shock proteins,” Cell Stress and Chaperones, vol. 14, no. 1, pp. 105–111, 2009.
[7]
E. A. Craig, “The heat shock response,” CRC Critical Reviews in Biochemistry, vol. 18, no. 3, pp. 239–280, 1985.
[8]
S. K. Calderwood, Y. Xie, X. Wang et al., “Signal transduction pathways leading to heat shock transcription,” Signal Transduction Insights, vol. 2, pp. 13–24, 2010.
[9]
F. M. Ritossa, “Experimental activation of specific loci in polytene chromosomes of Drosophila,” Experimental Cell Research, vol. 35, no. 3, pp. 601–607, 1964.
[10]
F. Ritossa, “A new puffing pattern induced by temperature shock and DNP in Drosophila,” Experientia, vol. 18, no. 12, pp. 571–573, 1962.
[11]
Y. Zhang and S. K. Calderwood, “Autophagy, protein aggregation and hyperthermia: a mini-review,” International Journal of Hyperthermia, vol. 27, no. 5, pp. 409–414, 2011.
[12]
G. C. Li and Z. Werb, “Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 10, pp. 3218–3222, 1982.
[13]
J. R. Subjeck, J. J. Sciandra, and R. J. Johnson, “Heat shock proteins and thermotolerance; a comparison of induction kinetics,” The British Journal of Radiology, vol. 55, no. 656, pp. 579–584, 1982.
[14]
V. L. Gabai, A. B. Meriin, D. D. Mosser et al., “Hsp70 prevents activation of stress kinases: a novel pathway of cellular thermotolerance,” The Journal of Biological Chemistry, vol. 272, no. 29, pp. 18033–18037, 1997.
[15]
M. Y. Sherman and A. L. Goldberg, “Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases,” Neuron, vol. 29, no. 1, pp. 15–32, 2001.
[16]
K. F. Winklhofer, J. Tatzelt, and C. Haass, “The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases,” EMBO Journal, vol. 27, no. 2, pp. 336–349, 2008.
[17]
S. K. Calderwood, A. Murshid, and T. Prince, “The shock of aging: molecular chaperones and the heat shock response in longevity and aging—a mini-review,” Gerontology, vol. 55, no. 5, pp. 550–558, 2009.
[18]
L. Whitesell and S. L. Lindquist, “HSP90 and the chaperoning of cancer,” Nature Reviews Cancer, vol. 5, no. 10, pp. 761–772, 2005.
[19]
D. R. Ciocca, A. P. Arrigo, and S. K. Calderwood, “Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update,” Archives of Toxicology, vol. 87, no. 1, pp. 19–48, 2013.
[20]
D. R. Ciocca and S. K. Calderwood, “Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications,” Cell Stress and Chaperones, vol. 10, no. 2, pp. 86–103, 2005.
[21]
J. Trepel, M. Mollapour, G. Giaccone, and L. Neckers, “Targeting the dynamic HSP90 complex in cancer,” Nature Reviews Cancer, vol. 10, no. 8, pp. 537–549, 2010.
[22]
L. Neckers, “Hsp90 inhibitors as novel cancer chemotherapeutic agents,” Trends in Molecular Medicine, vol. 8, no. 4, pp. S55–S61, 2002.
[23]
V. L. Gabai, J. A. Yaglom, T. Waldman, and M. Y. Sherman, “Heat shock protein Hsp72 controls oncogene-induced senescence pathways in cancer cells,” Molecular and Cellular Biology, vol. 29, no. 2, pp. 559–569, 2009.
[24]
C. O'Callaghan-Sunol, V. L. Gabai, and M. Y. Sherman, “Hsp27 modulates p53 signaling and suppresses cellular senescence,” Cancer Research, vol. 67, no. 24, pp. 11779–11788, 2007.
[25]
H. M. Beere, “‘The stress of dying’: the role of heat shock proteins in the regulation of apoptosis,” Journal of Cell Science, vol. 117, no. 13, pp. 2641–2651, 2004.
[26]
C. Wu, “Heat shock transcription factors: structure and regulation,” Annual Review of Cell and Developmental Biology, vol. 11, pp. 441–469, 1995.
[27]
C. Dai, L. Whitesell, A. B. Rogers, and S. Lindquist, “Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis,” Cell, vol. 130, no. 6, pp. 1005–1018, 2007.
[28]
M. A. Khaleque, A. Bharti, J. Gong et al., “Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1,” Oncogene, vol. 27, no. 13, pp. 1886–1893, 2008.
[29]
M. A. Khaleque, A. Bharti, D. Sawyer et al., “Induction of heat shock proteins by heregulin β1 leads to protection from apoptosis and anchorage-independent growth,” Oncogene, vol. 24, no. 43, pp. 6564–6573, 2005.
[30]
S. Santagata, R. Hu, N. U. Lin et al., “High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 45, pp. 18378–18383, 2011.
[31]
S. K. Calderwood, “HSF1, a versatile factor in tumorogenesis,” Current Molecular Medicine, vol. 12, no. 9, pp. 1102–1107, 2012.
[32]
J. L. Johnson, “Evolution and function of diverse Hsp90 homologs and cochaperone proteins,” Biochimica et Biophysica Acta, vol. 1823, no. 3, pp. 607–613, 2012.
[33]
H. Rampelt, M. P. Mayer, and B. Bukau, “Nucleotide exchange factors for Hsp70 chaperones,” Methods in Molecular Biology, vol. 787, pp. 83–91, 2011.
[34]
J. C. Young, V. R. Agashe, K. Siegers, and F. U. Hartl, “Pathways of chaperone-mediated protein folding in the cytosol,” Nature Reviews Molecular Cell Biology, vol. 5, no. 10, pp. 781–791, 2004.
[35]
J. C. Young, J. M. Barral, and F. U. Hartl, “More than folding: localized functions of cytosolic chaperones,” Trends in Biochemical Sciences, vol. 28, no. 10, pp. 541–547, 2003.
[36]
K. P. da Silva and J. C. Borges, “The molecular chaperone Hsp70 family members function by a bidirectional heterotrophic allosteric mechanism,” Protein and Peptide Letters, vol. 18, no. 2, pp. 132–142, 2011.
[37]
K. M. Flaherty, C. DeLuca-Flaherty, and D. B. McKay, “Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein,” Nature, vol. 346, no. 6285, pp. 623–628, 1990.
[38]
G. C. Flynn, T. G. Chappell, and J. E. Rothman, “Peptide binding and release by proteins implicated as catalysts of protein assembly,” Science, vol. 245, no. 4916, pp. 385–390, 1989.
[39]
R. Schlecht, A. H. Erbse, B. Bukau, and M. P. Mayer, “Mechanics of Hsp70 chaperones enables differential interaction with client proteins,” Nature Structural and Molecular Biology, vol. 18, no. 3, pp. 345–351, 2011.
[40]
S. K. Sharma, P. Christen, and P. Goloubinoff, “Disaggregating chaperones: an unfolding story,” Current Protein and Peptide Science, vol. 10, no. 5, pp. 432–446, 2009.
[41]
J. P. Chapple, J. van der Spuy, S. Poopalasundaram, and M. E. Cheetham, “Neuronal DnaJ proteins HSJ1a and HSJ1b: a role in linking the Hsp70 chaperone machine to the ubiquitin-proteasome system?” Biochemical Society Transactions, vol. 32, no. 4, pp. 640–642, 2004.
[42]
F. Hennessy, M. E. Cheetham, H. W. Dirr, and G. L. Blatch, “Analysis of the levels of conservation of the J domain among the various types of DnaJ-like proteins,” Cell Stress and Chaperones, vol. 5, no. 4, pp. 347–358, 2000.
[43]
F. Hennessy, W. S. Nicoll, R. Zimmermann, M. E. Cheetham, and G. L. Blatch, “Not all J domains are created equal: implications for the specificity of Hsp40-Hsp70 interactions,” Protein Science, vol. 14, no. 7, pp. 1697–1709, 2005.
[44]
J. N. Sterrenberg, G. L. Blatch, and A. L. Edkins, “Human DNAJ in cancer and stem cells,” Cancer Letters, vol. 312, no. 2, pp. 129–142, 2011.
[45]
F. Tsukahara and Y. Maru, “Bag1 directly routes immature BCR-ABL for proteasomal degradation,” Blood, vol. 116, no. 18, pp. 3582–3592, 2010.
[46]
A. Rosati, V. Graziano, V. de Laurenzi, M. Pascale, and M. C. Turco, “BAG3: a multifaceted protein that regulates major cell pathways,” Cell Death and Disease, vol. 2, no. 4, article e141, 2011.
[47]
S. Takayama, Z. Xie, and J. C. Reed, “An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators,” The Journal of Biological Chemistry, vol. 274, no. 2, pp. 781–786, 1999.
[48]
S. Takayama and J. C. Reed, “Molecular chaperone targeting and regulation by BAG family proteins,” Nature Cell Biology, vol. 3, no. 10, pp. E237–E241, 2001.
[49]
M. Kabani, C. McLellan, D. A. Raynes, V. Guerriero, and J. L. Brodsky, “HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor,” FEBS Letters, vol. 531, no. 2, pp. 339–342, 2002.
[50]
M. Kabani, J. M. Beckerich, and J. L. Brodsky, “Nucleotide exchange factor for the yeast Hsp70 molecular chaperone Ssa1p,” Molecular and Cellular Biology, vol. 22, no. 13, pp. 4677–4689, 2002.
[51]
C. Scheufler, A. Brinker, G. Bourenkov et al., “Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine,” Cell, vol. 101, no. 2, pp. 199–210, 2000.
[52]
H. Wegele, M. Haslbeck, J. Reinstein, and J. Buchner, “Sti1 is a novel activator of the Ssa proteins,” The Journal of Biological Chemistry, vol. 278, no. 28, pp. 25970–25976, 2003.
[53]
C. Prodromou, G. Siligardi, R. O'Brien et al., “Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones,” EMBO Journal, vol. 18, no. 3, pp. 754–762, 1999.
[54]
C. A. Ballinger, P. Connell, Y. Wu et al., “Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions,” Molecular and Cellular Biology, vol. 19, no. 6, pp. 4535–4545, 1999.
[55]
K. Liberek, C. Georgopoulos, and M. Zylicz, “Role of the Escherichia coli DnaK and DnaJ heat shock proteins in the initiation of bacteriophage λ DNA replication,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 18, pp. 6632–6636, 1988.
[56]
B. Panaretou, C. Prodromou, S. M. Roe et al., “ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo,” EMBO Journal, vol. 17, no. 16, pp. 4829–4836, 1998.
[57]
S. E. Jackson, “Hsp90: structure and function,” Topics in Current Chemistry, vol. 328, pp. 155–240, 2013.
[58]
M. F. N. Rosser, B. M. Trotta, M. R. Marshall, B. Berwin, and C. V. Nicchitta, “Adenosine nucleotides and the regulation of GRP94-client protein interactions,” Biochemistry, vol. 43, no. 27, pp. 8835–8845, 2004.
[59]
D. C. Altieri, G. S. Stein, J. B. Lian, and L. R. Languino, “TRAP-1, the mitochondrial Hsp90,” Biochimica et Biophysica Acta, vol. 1823, no. 3, pp. 767–773, 2012.
[60]
S. J. Felts, B. A. L. Owen, P. Nguyen, J. Trepel, D. B. Donner, and D. O. Toft, “The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties,” The Journal of Biological Chemistry, vol. 275, no. 5, pp. 3305–3312, 2000.
[61]
L. Neckers and S. P. Ivy, “Heat shock protein 90,” Current Opinion in Oncology, vol. 15, no. 6, pp. 419–424, 2003.
[62]
P. Workman, F. Burrows, L. Neckers, and N. Rosen, “Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress,” Annals of the New York Academy of Sciences, vol. 1113, pp. 202–216, 2007.
[63]
W. B. Pratt and D. O. Toft, “Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery,” Experimental Biology and Medicine, vol. 228, no. 2, pp. 111–133, 2003.
[64]
M. M. U. Ali, S. Mark Roe, C. K. Vaughan et al., “Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex,” Nature, vol. 440, no. 7087, pp. 1013–1017, 2006.
[65]
P. Meyer, C. Prodromou, B. Hu et al., “Structural and functional analysis of the middle segment of Hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions,” Molecular Cell, vol. 11, no. 3, pp. 647–658, 2003.
[66]
N. Wayne and D. N. Bolon, “Dimerization of Hsp90 is required for in vivo function: design and analysis of monomers and dimers,” The Journal of Biological Chemistry, vol. 282, no. 48, pp. 35386–35395, 2007.
[67]
N. Wayne, P. Mishra, and D. N. Bolon, “Hsp90 and client protein maturation,” Methods in Molecular Biology, vol. 787, pp. 33–44, 2011.
[68]
M. B. Cox and J. L. Johnson, “The role of p23, Hop, immunophilins, and other co-chaperones in regulating Hsp90 function,” Methods in Molecular Biology, vol. 787, pp. 45–66, 2011.
[69]
C. K. Vaughan, U. Gohlke, F. Sobott et al., “Structure of an Hsp90-Cdc37-Cdk4 complex,” Molecular Cell, vol. 23, no. 5, pp. 697–707, 2006.
[70]
S. H. McLaughlin, F. Sobott, Z. P. Yao et al., “The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins,” Journal of Molecular Biology, vol. 356, no. 3, pp. 746–758, 2006.
[71]
K. Richter, S. Walter, and J. Buchner, “The co-chaperone Sba1 connects the ATPase reaction of Hsp90 to the progression of the chaperone cycle,” Journal of Molecular Biology, vol. 342, no. 5, pp. 1403–1413, 2004.
[72]
N. Grammatikakis, J. H. Lin, A. Grammatikakis, P. N. Tsichlis, and B. H. Cochran, “p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function,” Molecular and Cellular Biology, vol. 19, no. 3, pp. 1661–1672, 1999.
[73]
P. J. Gray Jr., T. Prince, J. Cheng, M. A. Stevenson, and S. K. Calderwood, “Targeting the oncogene and kinome chaperone CDC37,” Nature Reviews Cancer, vol. 8, no. 7, pp. 491–495, 2008.
[74]
A. K. Mandal, M. A. Theodoraki, N. B. Nillegoda, and A. J. Caplan, “Role of molecular chaperones in biogenesis of the protein kinome,” Methods in Molecular Biology, vol. 787, pp. 75–81, 2012.
[75]
R. Matts and A. J. Caplan, Cdc37 and Protein Kinase Folding, Springer, Dordrecht, The Netherlands, 2007.
[76]
M. G. Catlett and K. B. Kaplan, “Sgt1p is a unique co-chaperone that acts as a client adaptor to link Hsp90 to Skp1p,” The Journal of Biological Chemistry, vol. 281, no. 44, pp. 33739–33748, 2006.
[77]
M. P. Mayer, R. Nikolay, and B. Bukau, “Aha, another regulator for Hsp90 chaperones,” Molecular Cell, vol. 10, no. 6, pp. 1255–1256, 2002.
[78]
M. Retzlaff, F. Hagn, L. Mitschke et al., “Asymmetric activation of the Hsp90 dimer by its cochaperone Aha1,” Molecular Cell, vol. 37, no. 3, pp. 344–354, 2010.
[79]
J. van der Spuy, M. E. Cheetham, H. W. Dirr, and G. L. Blatch, “The cochaperone murine stress-inducible protein 1: overexpression, purification, and characterization,” Protein Expression and Purification, vol. 21, no. 3, pp. 462–469, 2001.
[80]
A. B. Schmid, S. Lagleder, M. A. Grawert et al., “The architecture of functional modules in the Hsp90 co-chaperone Sti1/Hop,” EMBO Journal, vol. 31, pp. 1506–1517, 2012.
[81]
M. Zhang, M. Windheim, S. M. Roe et al., “Chaperoned ubiquitylation—crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex,” Molecular Cell, vol. 20, no. 4, pp. 525–538, 2005.
[82]
M. Stankiewicz, R. Nikolay, V. Rybin, and M. P. Mayer, “CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70-bound substrates,” FEBS Journal, vol. 277, no. 16, pp. 3353–3367, 2010.
[83]
S. Carra, S. J. Seguin, and J. Landry, “HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy,” Autophagy, vol. 4, no. 2, pp. 237–239, 2008.
[84]
M. Gamerdinger, A. M. Kaya, U. Wolfrum, A. M. Clement, and C. Behl, “BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins,” EMBO Reports, vol. 12, no. 2, pp. 149–156, 2011.
[85]
A. A. Duina, J. A. Marsh, R. B. Kurtz, H. C. J. Chang, S. Lindquist, and R. F. Gaber, “The peptidyl-prolyl isomerase domain of the CyP-40 cyclophilin homolog Cpr7 is not required to support growth or glucocorticoid receptor activity in Saccharomyces cerevisiae,” The Journal of Biological Chemistry, vol. 273, no. 18, pp. 10819–10822, 1998.
[86]
D. Mok, R. K. Allan, A. Carrello, K. Wangoo, M. D. Walkinshaw, and T. Ratajczak, “The chaperone function of cyclophilin 40 maps to a cleft between the prolyl isomerase and tetratricopeptide repeat domains,” FEBS Letters, vol. 580, no. 11, pp. 2761–2768, 2006.
[87]
C. Demonacos, M. Krstic-Demonacos, and N. B. la Thangue, “A TPR motif cofactor contributes to p300 activity in the p53 response,” Molecular Cell, vol. 8, no. 1, pp. 71–84, 2001.
[88]
C. Demonacos, M. Krstic-Demonacos, L. Smith et al., “A new effector pathway links ATM kinase with the DNA damage response,” Nature Cell Biology, vol. 6, no. 10, pp. 968–976, 2004.
[89]
L. Brive, S. Takayama, K. Briknarová et al., “The carboxyl-terminal lobe of Hsc70 ATPase domain is sufficient for binding to BAG1,” Biochemical and Biophysical Research Communications, vol. 289, no. 5, pp. 1099–1105, 2001.
[90]
J. K. Stuart, D. G. Myszka, L. Joss et al., “Characterization of interactions between the anti-apoptotic protein BAG-1 and Hsc70 molecular chaperones,” The Journal of Biological Chemistry, vol. 273, no. 35, pp. 22506–22514, 1998.
[91]
S. Franceschelli, A. Rosati, R. Lerose, S. de Nicola, M. C. Turco, and M. Pascale, “bag3 gene expression is regulated by heat shock factor 1,” Journal of Cellular Physiology, vol. 215, no. 3, pp. 575–577, 2008.
[92]
S. Aveic, M. Pigazzi, and G. Basso, “BAG1: the guardian of anti-apoptotic proteins in acute myeloid leukemia,” PLoS ONE, vol. 6, no. 10, Article ID e26097, 2011.
[93]
M. Ammirante, A. Rosati, C. Arra et al., “IKKγ protein is a target of BAG3 regulatory activity in human tumor growth,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 16, pp. 7497–7502, 2010.
[94]
Y. Shomura, Z. Dragovic, H. C. Chang et al., “Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange,” Molecular Cell, vol. 17, no. 3, pp. 367–379, 2005.
[95]
S. Alberti, K. B？hse, V. Arndt, A. Schmitz, and J. H？hfeld, “The cochaperone HspBP1 inhibits the CHIP ubiquitin ligase and stimulates the maturation of the cystic fibrosis transmembrane conductance regulator,” Molecular Biology of the Cell, vol. 15, no. 9, pp. 4003–4010, 2004.
[96]
A. P. Souza, C. Albuquerque, C. Torronteguy et al., “HspBP1 levels are elevated in breast tumor tissue and inversely related to tumor aggressiveness,” Cell Stress and Chaperones, vol. 14, no. 3, pp. 301–310, 2009.
[97]
S. Tanimura, A. I. Hirano, J. Hashizume et al., “Anticancer drugs up-regulate HspBP1 and thereby antagonize the prosurvival function of Hsp70 in tumor cells,” The Journal of Biological Chemistry, vol. 282, no. 49, pp. 35430–35439, 2007.
[98]
N. Fehrenbacher and M. J？？ttel？, “Lysosomes as targets for cancer therapy,” Cancer Research, vol. 65, no. 8, pp. 2993–2995, 2005.
[99]
J. Nylandsted, M. Gyrd-Hansen, A. Danielewicz et al., “Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization,” Journal of Experimental Medicine, vol. 200, no. 4, pp. 425–435, 2004.
[100]
D. Straus, W. Walter, and C. A. Gross, “DnaK, DnaJ, and GrpE heat shock proteins negatively regulate heat shock gene expression by controlling the synthesis and stability of σ32,” Genes and Development, vol. 4, no. 12, pp. 2202–2209, 1990.
[101]
H. Isomoto, M. Oka, Y. Yano et al., “Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer,” Cancer Letters, vol. 198, no. 2, pp. 219–228, 2003.
[102]
A. Mitra, R. A. Fillmore, B. J. Metge et al., “Large isoform of MRJ (DNAJB6) reduces malignant activity of breast cancer,” Breast Cancer Research, vol. 10, no. 2, article R22, 2008.
[103]
A. Mitra, L. A. Shevde, and R. S. Samant, “Multi-faceted role of HSP40 in cancer,” Clinical and Experimental Metastasis, vol. 26, no. 6, pp. 559–567, 2009.
[104]
I. Canamasas, A. Debes, P. G. Natali, and U. Kurzik-Dumke, “Understanding human cancer using Drosophila. Tid47, a cytosolic product of the DnaJ-like tumor suppressor gene l(2)tid, is a novel molecular partner of patched related to skin cancer,” The Journal of Biological Chemistry, vol. 278, no. 33, pp. 30952–30960, 2003.
[105]
U. Kurzik-Dumke, D. Gundacker, M. Rentrop, and E. Gateff, “Tumor suppression in Drosophila is causally related to the function of the lethal(2)tumorous imaginal discs gene, a dnaJ homolog,” Developmental Genetics, vol. 16, no. 1, pp. 64–76, 1995.
[106]
P. E. Carrigan, L. A. Sikkink, D. F. Smith, and M. Ramirez-Alvarado, “Domain:domain interactions within Hop, the Hsp70/Hsp90 organizing protein, are required for protein stability and structure,” Protein Science, vol. 15, no. 3, pp. 522–532, 2006.
[107]
H. Kubota, S. Yamamoto, E. Itoh et al., “Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma,” Cell Stress and Chaperones, vol. 15, no. 6, pp. 1003–1011, 2010.
[108]
W. Sun, B. Xing, Y. Sun et al., “Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis,” Molecular and Cellular Proteomics, vol. 6, no. 10, pp. 1798–1808, 2007.
[109]
N. Walsh, A. Larkin, N. Swan et al., “RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation,” Cancer Letters, vol. 306, no. 2, pp. 180–189, 2011.
[110]
B. C. Freeman, S. J. Felts, D. O. Toft, and K. R. Yamamoto, “The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies,” Genes and Development, vol. 14, no. 4, pp. 422–434, 2000.
[111]
N. E. Simpson, W. M. Lambert, R. Watkins et al., “High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance,” Cancer Research, vol. 70, no. 21, pp. 8446–8456, 2010.
[112]
V. Reebye, L. Q. Cano, D. N. Lavery et al., “Role of the HSP90-associated cochaperone p23 in enhancing activity of the androgen receptor and significance for prostate cancer,” Molecular Endocrinology, vol. 26, no. 10, pp. 1694–1706, 2012.
[113]
T. Prince and L. Neckers, “A network of its own: the unique interactome of the Hsp90 cochaperone, Sba1/p23,” Molecular Cell, vol. 43, no. 2, pp. 159–160, 2011.
[114]
X. Liu, L. Zou, L. Zhu et al., “miRNA mediated up-regulation of cochaperone p23 acts as an anti-apoptotic factor in childhood acute lymphoblastic leukemia,” Leukemia Research, vol. 36, no. 9, pp. 1098–1104, 2012.
[115]
C. A. Patwardhan, A. Fauq, L. B. Peterson, C. Miller, B. S. Blagg, and A. Chadli, “Gedunin inactivates the co-chaperone p23 causing cancer cell death by apoptosis,” The Journal of Biological Chemistry, vol. 288, no. 10, pp. 7313–7325, 2013.
[116]
M. Zabka, W. Le？niak, W. Prus, J. Ku？nicki, and A. Filipek, “Sgt1 has co-chaperone properties and is up-regulated by heat shock,” Biochemical and Biophysical Research Communications, vol. 370, no. 1, pp. 179–183, 2008.
[117]
J. Stuttmann, J. E. Parker, and L. D. No？l, “Staying in the fold: the SGT1/chaperone machinery in maintenance and evolution of leucine-rich repeat proteins,” Plant Signaling and Behavior, vol. 3, no. 5, pp. 283–285, 2008.
[118]
M. Zhang, Y. Kadota, C. Prodromou, K. Shirasu, and L. H. Pearl, “Structural basis for assembly of Hsp90-Sgt1-CHORD protein complexes: implications for chaperoning of NLR innate immunity receptors,” Molecular Cell, vol. 39, no. 2, pp. 269–281, 2010.
[119]
A. E. Davies and K. B. Kaplan, “Hsp90-Sgt1 and Skp1 target human Mis12 complexes to ensure efficient formation of kinetochore-microtubule binding sites,” Journal of Cell Biology, vol. 189, no. 2, pp. 261–274, 2010.
[120]
L. Stepanova, M. Finegold, F. DeMayo, E. V. Schmidt, and J. W. Harper, “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,” Molecular and Cellular Biology, vol. 20, no. 12, pp. 4462–4473, 2000.
[121]
L. Stepanova, G. Yang, F. DeMayo et al., “Induction of human Cdc37 in prostate cancer correlates with the ability of targeted Cdc37 expression to promote prostatic hyperplasia,” Oncogene, vol. 19, no. 18, pp. 2186–2193, 2000.
[122]
S. Casas, J. Ollila, A. Aventín, M. Vihinen, J. Sierra, and S. Knuutila, “Changes in apoptosis-related pathways in acute myelocytic leukemia,” Cancer Genetics and Cytogenetics, vol. 146, no. 2, pp. 89–101, 2003.
[123]
F. Feo, M. R. de Miglio, M. M. Simile et al., “Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition,” Biochimica et Biophysica Acta, vol. 1765, no. 2, pp. 126–147, 2006.
[124]
Y. Katayama, A. Sakai, Y. Okikawa et al., “Cyclin D1 overexpression is not a specific grouping marker, but may collaborate with CDC37 in myeloma cells,” International Journal of Oncology, vol. 25, no. 3, pp. 579–595, 2004.
[125]
M. A. Thompson, J. Stumph, S. E. Henrickson et al., “Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas,” Human Pathology, vol. 36, no. 5, pp. 494–504, 2005.
[126]
A. J. Caplan, A. K. Mandal, and M. A. Theodoraki, “Molecular chaperones and protein kinase quality control,” Trends in Cell Biology, vol. 17, no. 2, pp. 87–92, 2007.
[127]
A. K. Mandal, P. Lee, J. A. Chen et al., “Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation,” Journal of Cell Biology, vol. 176, no. 3, pp. 319–328, 2007.
[128]
P. J. Gray Jr., M. A. Stevenson, and S. K. Calderwood, “Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells,” Cancer Research, vol. 67, no. 24, pp. 11942–11950, 2007.
[129]
J. R. Smith, P. A. Clarke, E. De Billy, and P. Workman, “Silencing the cochaperone CDC37 destabilizes kinase clients and sensitizes cancer cells to HSP90 inhibitors,” Oncogene, vol. 28, no. 2, pp. 157–169, 2009.
[130]
K. Robzyk, H. Oen, G. Buchanan et al., “Uncoupling of hormone-dependence from chaperone-dependence in the L701H mutation of the androgen receptor,” Molecular and Cellular Endocrinology, vol. 268, no. 1-2, pp. 67–74, 2007.
[131]
L. H. Pearl and C. Prodromou, “Structure, function, and mechanism of the Hsp90 molecular chaperone,” Advances in Protein Chemistry, vol. 59, pp. 157–186, 2001.
[132]
A. I. Su, T. Wiltshire, S. Batalov et al., “A gene atlas of the mouse and human protein-encoding transcriptomes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 16, pp. 6062–6067, 2004.
[133]
J. L. Holmes, S. Y. Sharp, S. Hobbs, and P. Workman, “Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin,” Cancer Research, vol. 68, no. 4, pp. 1188–1197, 2008.
[134]
J. P. Schülke, G. M. Wochnik, I. Lang-Rollin et al., “Differential impact of tetratricopeptide repeat proteins on the steroid hormone receptors,” PloS ONE, vol. 5, no. 7, p. e11717, 2010.
[135]
J. G. Scammell, W. B. Denny, D. L. Valentine, and D. F. Smith, “Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates,” General and Comparative Endocrinology, vol. 124, no. 2, pp. 152–165, 2001.
[136]
W. B. Denny, D. L. Valentine, P. D. Reynolds, D. F. Smith, and J. G. Scammell, “Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding,” Endocrinology, vol. 141, no. 11, pp. 4107–4113, 2000.
[137]
D. L. Riggs, M. B. Cox, H. L. Tardif, M. Hessling, J. Buchner, and D. F. Smith, “Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling,” Molecular and Cellular Biology, vol. 27, no. 24, pp. 8658–8669, 2007.
[138]
H. D. McKeen, D. J. Brennan, S. Hegarty et al., “The emerging role of FK506-binding proteins as cancer biomarkers: a focus on FKBPL,” Biochemical Society Transactions, vol. 39, no. 2, pp. 663–668, 2011.
[139]
M. Chinkers, “Targeting of a distinctive protein-serine phosphatase to the protein kinase-like domain of the atrial natriuretic peptide receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 23, pp. 11075–11079, 1994.
[140]
T. D. Hinds Jr., L. A. Stechschulte, H. A. Cash et al., “Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma (PPARγ),” The Journal of Biological Chemistry, vol. 286, no. 50, pp. 42911–42922, 2011.
[141]
T. D. Hinds Jr. and E. R. Sánchez, “Protein phosphatase 5,” International Journal of Biochemistry and Cell Biology, vol. 40, no. 11, pp. 2358–2362, 2008.
[142]
M. Mollapour, S. Tsutsumi, A. W. Truman et al., “Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity,” Molecular Cell, vol. 41, no. 6, pp. 672–681, 2011.
[143]
M. Mollapour and L. Neckers, “Post-translational modifications of Hsp90 and their contributions to chaperone regulation,” Biochimica et Biophysica Acta, vol. 1823, no. 3, pp. 648–655, 2012.
[144]
S. K. Wandinger, M. H. Suhre, H. Wegele, and J. Buchner, “The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90,” EMBO Journal, vol. 25, no. 2, pp. 367–376, 2006.
[145]
C. K. Vaughan, M. Mollapour, J. R. Smith et al., “Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37,” Molecular Cell, vol. 31, no. 6, pp. 886–895, 2008.
[146]
T. Wechsler, B. P. C. Chen, R. Harper et al., “DNA-PKcs function regulated specifically by protein phosphatase 5,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 5, pp. 1247–1252, 2004.
[147]
Y. Kang, H. M. Cheong, J. H. Lee et al., “Protein phosphatase 5 is necessary for ATR-mediated DNA repair,” Biochemical and Biophysical Research Communications, vol. 404, no. 1, pp. 476–481, 2011.
[148]
M. Poetsch, T. Dittberner, J. K. Cowell, and C. Woenckhaus, “TTC4, a novel candidate tumor suppressor gene at 1p31 is often mutated in malignant melanoma of the skin,” Oncogene, vol. 19, no. 50, pp. 5817–5820, 2000.
[149]
G. Su, T. Roberts, and J. K. Cowell, “TTC4, a novel human gene containing the tetratricopeptide repeat and mapping to the region of chromosome 1p31 that is frequently deleted in sporadic breast cancer,” Genomics, vol. 55, no. 2, pp. 157–163, 1999.
[150]
R. I. Dmitriev, I. A. Okkelman, R. A. Abdulin, M. I. Shakhparonov, and N. B. Pestov, “Nuclear transport of protein TTC4 depends on the cell cycle,” Cell and Tissue Research, vol. 336, no. 3, pp. 521–527, 2009.
[151]
R. I. Dmitriev, T. V. Korneenko, A. A. Bessonov, M. I. Shakhparonov, N. N. Modyanov, and N. B. Pestov, “Characterization of hampin/MSL1 as a node in the nuclear interactome,” Biochemical and Biophysical Research Communications, vol. 355, no. 4, pp. 1051–1057, 2007.
[152]
R. D. Moir and I. M. Willis, “Tetratricopeptide repeats of TFC4 and a limiting step in the assembly of the initiation factor TFIIIB,” Advances in Protein Chemistry, vol. 67, pp. 93–121, 2004.
[153]
G. Crevel, D. Bennett, and S. Cotterill, “The human TPR protein TTC4 is a putative Hsp90 co-chaperone which interacts with CDC6 and shows alterations in transformed cells,” PLoS ONE, vol. 3, no. 3, Article ID e1737, 2008.
[154]
D. Xu, L. P. Zalmas, and N. B. la Thangue, “A transcription cofactor required for the heat-shock response,” EMBO Reports, vol. 9, no. 7, pp. 662–669, 2008.
[155]
D. Xu and N. B. la Thangue, “Strap: a versatile transcription co-factor,” Cell Cycle, vol. 7, no. 16, pp. 2456–2457, 2008.
[156]
Y. Zhang, A. Murshid, T. Prince, and S. K. Calderwood, “Protein kinase A regulates molecular chaperone transcription and protein aggregation,” PLoS ONE, vol. 6, no. 12, Article ID e28950, 2011.
[157]
L. Davies, E. Paraskevopoulou, M. Sadeq et al., “Regulation of glucocorticoid receptor activity by a stress responsive transcriptional cofactor,” Molecular Endocrinology, vol. 25, no. 1, pp. 58–71, 2011.
[158]
N. Kuzhandaivelu, Y. S. Cong, C. Inouye, W. M. Yang, and E. Seto, “XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation,” Nucleic Acids Research, vol. 24, no. 23, pp. 4741–4750, 1996.
[159]
W. Cai, T. V. Kramarova, P. Berg, M. Korbonits, and I. Pongratz, “The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α,” PLoS ONE, vol. 6, no. 10, Article ID e25201, 2011.
[160]
Z. Yin, E. C. Henry, and T. A. Gasiewicz, “(-)-epigallocatechin-3-gallate is a novel Hsp90 inhibitor,” Biochemistry, vol. 48, no. 2, pp. 336–345, 2009.
[161]
A. Mazumdar, R. A. Wang, S. K. Mishra et al., “Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor,” Nature Cell Biology, vol. 3, no. 1, pp. 30–37, 2001.
[162]
P. Romano, Z. He, and S. Luan, “Introducing immunophilins. From organ transplantation to plant biology,” Plant Physiology, vol. 134, no. 4, pp. 1241–1243, 2004.
[163]
A. A. Duina, H. C. J. Chang, J. A. Marsh, S. Lindquist, and R. F. Gaber, “A cyclophilin function in Hsp90-dependent signal transduction,” Science, vol. 274, no. 5293, pp. 1713–1715, 1996.
[164]
S. Periyasamy, M. Warrier, M. P. M. Tillekeratne, W. Shou, and E. R. Sanchez, “The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms,” Endocrinology, vol. 148, no. 10, pp. 4716–4726, 2007.
[165]
S. Periyasamy, T. Hinds Jr., L. Shemshedini, W. Shou, and E. R. Sanchez, “FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A,” Oncogene, vol. 29, no. 11, pp. 1691–1701, 2010.
[166]
P. Kumar, P. J. Mark, B. K. Ward, R. F. Minchin, and T. Ratajczak, “Estradiol-regulated expression of the immunophilins cyclophilin 40 and FKBP52 in MCF-7 breast cancer cells,” Biochemical and Biophysical Research Communications, vol. 284, no. 1, pp. 219–225, 2001.
[167]
G. M. Wochnik, J. Rüegg, G. A. Abel, U. Schmidt, F. Holsboer, and T. Rein, “FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells,” The Journal of Biological Chemistry, vol. 280, no. 6, pp. 4609–4616, 2005.
[168]
H. D. McKeen, K. McAlpine, A. Valentine et al., “A novel FK506-like binding protein interacts with the glucocorticoid receptor and regulates steroid receptor signaling,” Endocrinology, vol. 149, no. 11, pp. 5724–5734, 2008.
[169]
H. D. McKeen, C. Byrne, P. V. Jithesh et al., “FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy,” Cancer Research, vol. 70, no. 3, pp. 1090–1100, 2010.
[170]
A. M. Velasco, K. A. Gillis, Y. Li et al., “Identification and validation of novel androgen-regulated genes in prostate cancer,” Endocrinology, vol. 145, no. 8, pp. 3913–3924, 2004.
[171]
L. Ni, C. S. Yang, D. Gioeli, H. Frierson, D. O. Toft, and B. M. Paschal, “FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells,” Molecular and Cellular Biology, vol. 30, no. 5, pp. 1243–1253, 2010.
[172]
D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000.
[173]
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
[174]
L. Neckers and P. Workman, “Hsp90 molecular chaperone inhibitors: are we there yet?” Clinical Cancer Research, vol. 18, pp. 64–76, 2012.
[175]
L. Whitesell, E. G. Mimnaugh, B. de Costa, C. E. Myers, and L. M. Neckers, “Inhibition of heat shock protein HSP90-pp60(v-src) heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 18, pp. 8324–8328, 1994.
[176]
S. Modi, A. Stopeck, H. Linden et al., “HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab,” Clinical Cancer Research, vol. 17, no. 15, pp. 5132–5139, 2011.
[177]
S. Modi, A. T. Stopeck, M. S. Gordon et al., “Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2-overexpressing breast cancer: a phase I dose-escalation study,” Journal of Clinical Oncology, vol. 25, no. 34, pp. 5410–5417, 2007.
[178]
M. Rohde, M. Daugaard, M. H. Jensen, K. Helin, J. Nylandsted, and M. J？？ttel？, “Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms,” Genes and Development, vol. 19, no. 5, pp. 570–582, 2005.
[179]
R. Wadhwa, K. Taira, and S. C. Kaul, “An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where?” Cell Stress and Chaperones, vol. 7, no. 3, pp. 309–316, 2002.
[180]
M. V. Powers, P. A. Clarke, and P. Workman, “Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis,” Cancer Cell, vol. 14, no. 3, pp. 250–262, 2008.
[181]
M. V. Powers, K. Jones, C. Barillari, I. Westwood, R. L. M. van Montfort, and P. Workman, “Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone?” Cell Cycle, vol. 9, no. 8, pp. 1542–1550, 2010.
[182]
H. Hieronymus, J. Lamb, K. N. Ross et al., “Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators,” Cancer Cell, vol. 10, no. 4, pp. 321–330, 2006.
[183]
T. Zhang, A. Hamza, X. Cao et al., “A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells,” Molecular Cancer Therapeutics, vol. 7, no. 1, pp. 162–170, 2008.
[184]
A. Salminen, M. Lehtonen, T. Paimela, and K. Kaarniranta, “Celastrol: molecular targets of Thunder God Vine,” Biochemical and Biophysical Research Communications, vol. 394, no. 3, pp. 439–442, 2010.
