Abstract
Molecular chaperones or so-called heat shock proteins act as central integrators of protein homeostasis within cells. Among the major chaperones, however, Hsp90 is unique because it is not required for the biogenesis of most polypeptides. Instead, it oversees a surprisingly diverse network of conformationally labile client substrates that regulate signaling pathways and gene expression. Many of the processes modulated by Hsp90 are dysregulated in cancer cells including cell cycle control, apoptosis and chromatin re-modeling. Over the past decade, much of the progress achieved in understanding the complex role of Hsp90 in cancer biology has been made possible by the discovery of several natural product antitumor antibiotics that selectively inhibit Hsp90 function. These compounds have the ability to accomplish what most molecularly targeted anticancer therapies do not –the simultaneous disruption of multiple processes critical to tumor cell growth and survival. Now, great enthusiasm exists over the prospect of targeting Hsp90 function to treat cancer. New chemotypes with improved pharmacology are being developed and clinical trials have demonstrated that Hsp90 function can be inhibited in cancer patients without undue acute toxicity. Remarkable progress has been made, but much more remains to be learned if we are to succeed in the challenge of defining safe and effective ways to exploit Hsp90 inhibition in the treatment of patients
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References
Ali, M. M., Roe, S. M., Vaughan, C. K., Meyer, P., Panaretou, B., Piper, P. W., Prodromou, C. and Pearl, L. H. (2006) Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013–7.
Allan, R. K., Mok, D., Ward, B. K. and Ratajczak, T. (2006) Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: evidence that coumarin antibiotics disrupt Hsp90 dimerization. J Biol Chem 281, 7161–71.
Bagatell, R., Gore, L., Egorin, M. and et al., e. (2007) Phase I and Pharmacokinetic Study of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) in Patients with Recurrent or Refractory Pediatric Solid Tumors. Clin Cancer Res 13, 1783–1788.
Bagatell, R., Paine-Murrieta, G., Taylor, C., Pulcini, E., Akinaga, S., Benjamin, I. and Whitesell, L. (2000) Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of Hsp90 binding agents. Clin Cancer Res 6, 3312–3318.
Bagatell, R. and Whitesell, L. (2004) Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther 3, 1021–30.
Bali, P., Pranpat, M., Swaby, R., Fiskus, W., Yamaguchi, H., Balasis, M., Rocha, K., Wang, H. G., Richon, V. and Bhalla, K. (2005) Activity of suberoylanilide hydroxamic Acid against human breast cancer cells with amplification of her-2. Clin Cancer Res 11, 6382–9.
Banerji, U., O’Donnell, A., Scurr, M., Pacey, S., Stapleton, S., Asad, Y., Simmons, L., Maloney, A., Raynaud, F., Campbell, M., Walton, M., Lakhani, S., Kaye, S., Workman, P. and Judson, I. (2005) Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17Demethoxygeldanamycin in Patients With Advanced Malignancies. J Clin Oncol 23, 4152–4161.
Barker, C. R., Hamlett, J., Pennington, S. R., Burrows, F., Lundgren, K., Lough, R., Watson, A. J. and Jenkins, J. R. (2006) The topoisomerase II-Hsp90 complex: a new chemotherapeutic target? Int J Cancer 118, 2685–93.
Birnby, D. A., Link, E. M., Vowels, J. J., Tian, H., Colacurcio, P. L. and Thomas, J. H. (2000) A transmembrane guanylyl cyclase (DAF-11) and Hsp90 (DAF-21) regulate a common set of chemosensory behaviors in caenorhabditis elegans. Genetics 155, 85–104.
Blagosklonny, M. V., Toretsky, J., Bohen, S. and Neckers, L. (1996) Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90. Proc. Natl. Acad. Sci. USA 93, 8379–83.
Borkovich, K. A., Farrelly, F. W., Finkelstein, D. B., Taulien, J. and Lindquist, S. (1989) Hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures. Mol. Cell. Biol. 9, 3919–30.
Boudeau, J., Deak, M., Lawlor, M. A., Morrice, N. A. and Alessi, D. R. (2003) Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability. Biochem J 370, 849–57.
Burlison, J. A., Neckers, L., Smith, A. B., Maxwell, A. and Blagg, B. S. (2006) Novobiocin: redesigning a DNA gyrase inhibitor for selective inhibition of hsp90. J Am Chem Soc 128, 15529–36.
Castro, J. E., Prada, C. E., Loria, O., Kamal, A., Chen, L., Burrows, F. J. and Kipps, T. J. (2005) ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 106, 2506–12.
Chadli, A., Graham, J. D., Abel, M. G., Jackson, T. A., Gordon, D. F., Wood, W. M., Felts, S. J., Horwitz, K. B. and Toft, D. (2006) GCUNC-45 is a novel regulator for the progesterone receptor/hsp90 chaperoning pathway. Mol Cell Biol 26, 1722–30.
Clarke, P. A., Hostein, I., Banerji, U., Stefano, F. D., Maloney, A., Walton, M., Judson, I. and Workman, P. (2000) Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone. Oncogene. 19, 4125–33.
Csermely, P., Schnaider, T., Soti, C., Prohaskka, Z. and Nardai, G. (1998) The 90-kDa molecular chaperone family: Structure, function, and clinical applications. A comprehensive review. Pharmacol. Ther. 79, 129–168.
Cullinan, S. B. and Whitesell, L. (2006) Heat shock protein 90: a unique chemotherapeutic target. Semin Oncol 33, 457–65.
Dutta, R. and Inouye, M. (2000) GHKL, an emergent ATPase/kinase superfamily. Trends Biochem. Sci. 25, 24–28.
Feinberg, A. P., Ohlsson, R. and Henikoff, S. (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7, 21–33.
Flom, G., Weekes, J. and Johnson, J. L. (2005) Novel interaction of the Hsp90 chaperone machine with Ssl2, an essential DNA helicase in Saccharomyces cerevisiae. Curr Genet 47, 368–80.
Freeman, B. C. and Yamamoto, K. R. (2002) Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296, 2232–5.
Garnier, C., Lafitte, D., Tsvetkov, P. O., Barbier, P., Leclerc-Devin, J., Millot, J. M., Briand, C., Makarov, A. A., Catelli, M. G. and Peyrot, V. (2002) Binding of ATP to heat shock protein 90: evidence for an ATP-binding site in the C-terminal domain. J Biol Chem 277, 12208–14.
Gatenby, R. A. and Vincent, T. L. (2003) An evolutionary model of carcinogenesis. Cancer Res. 63, 6212–6220.
Ge, J., Normant, E., Porter, J. R., Ali, J. A., Dembski, M. S., Gao, Y., Georges, A. T., Grenier, L., Pak, R. H., Patterson, J., Sydor, J. R., Tibbitts, T. T., Tong, J. K., Adams, J. and Palombella, V. J. (2006) Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 49, 4606–15.
George, P., Bali, P., Annavarapu, S., Scuto, A., Fiskus, W., Guo, F., Sigua, C., Sondarva, G., Moscinski, L., Atadja, P. and Bhalla, K. (2005) Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 105, 1768–76.
Goetz, M. P., Toft, D., Reid, J., Ames, M., Stensgard, B., Safgren, S., Adjei, A. A., Sloan, J., Atherton, P., Vasile, V., Salazaar, S., Adjei, A., Croghan, G. and Erlichman, C. (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23, 1078–87.
Goetz, M. P., Toft, D. O., Ames, M. M. and Erlichman, C. (2003) The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol 14, 1169–76.
Gooljarsingh, L. T., Fernandes, C., Yan, K., Zhang, H., Grooms, M., Johanson, K., Sinnamon, R. H., Kirkpatrick, R. B., Kerrigan, J., Lewis, T., Arnone, M., King, A. J., Lai, Z., Copeland, R. A. and Tummino, P. J. (2006) A biochemical rationale for the anticancer effects of Hsp90 inhibitors: slow, tight binding inhibition by geldanamycin and its analogues. Proc Natl Acad Sci U S A 103, 7625–30.
Gorre, M. E., Ellwood-Yen, K., Chiosis, G., Rosen, N. and Sawyers, C. L. (2002) BCR-ABL point mutants isolated from patients with imatinib mesylateresistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 100, 3041–4.
Grammatikakis, N., Vultur, A., Ramana, C. V., Siganou, A., Schweinfest, C. W., Watson, D. K. and Raptis, L. (2002) The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation. J Biol Chem 277, 8312–20.
Grem, J. L., Morrison, G., Guo, X. D., Agnew, E., Takimoto, C. H., Thomas, R., Szabo, E., Grochow, L., Grollman, F., Hamilton, J. M., Neckers, L. and Wilson, R. H. (2005) Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23, 1885–93.
Guo, W., Reigan, P., Siegel, D., Zirrolli, J., Gustafson, D. and Ross, D. (2006) The bioreduction of a series of benzoquinone ansamycins by NAD(P)H:quinone oxidoreductase 1 to more potent heat shock protein 90 inhibitors, the hydroquinone ansamycins. Mol Pharmacol 70, 1194–203.
Guo, Y., Guettouche, T., Fenna, M., Boellmann, F., Pratt, W. B., Toft, D. O., Smith, D. F. and Voellmy, R. (2001) Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex. J. Biol. Chem. 276, 45791–9.
Hamamoto, R., Furukawa, Y., Morita, M., Iimura, Y., Silva, F. P., Li, M., Yagyu, R. and Nakamura, Y. (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6, 731–40.
Hansen, R. K., Oesterreich, S., Lemieux, P., Sarge, K. D. and Fuqua, S. A. (1997) Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells. Biochem. Biophys. Res. Comm. 239, 851–6.
Hegde, R., Zuo, J., Voellmy, R. and Welch, W. (1995) Short circuiting stress protein expression via a tyrosine kinase inhibitor, herbimycin A. J. Cell Physiol 165, 186.
Ibrahim, N. O., Hahn, T., Franke, C., Stiehl, D. P., Wirthner, R., Wenger, R. H. and Katschinski, D. M. (2005) Induction of the hypoxia-inducible factor system by low levels of heat shock protein 90 inhibitors. Cancer Res 65, 11094–100.
Isaacs, J. S., Jung, Y. J., Mimnaugh, E. G., Martinez, A., Cuttitta, F. and Neckers, L. M. (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 277, 29936–44.
Isaacs, J. S., Xu, W. and Neckers, L. (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3, 213–7.
Itoh, H., Ogura, M., Komatsuda, A., Wakui, H., Miura, A. and Tashima, Y. (1999) A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90. Biochem. J. 343, 697–703.
Jameel, A., Skilton, R. A., Campbell, T. A., Chander, S. K., Coombes, R. C. and Luqmani, Y. A. (1992) Clinical and biological significance of Hsp90a in human breast cancer. Int. J. Cancer 50, 409–415.
Janin, Y. L. (2005) Heat shock protein 90 inhibitors. A text book example of medicinal chemistry? J Med Chem 48, 7503–12.
Jerome, V., Leger, J., Devin, J., Baulieu, E. E. and Catelli, M. G. (1991) Growth factors acting via tyrosine kinase receptors induce HSP90 alpha gene expression. Growth Factors 4, 317–27.
Kamal, A., Boehm, M. F. and Burrows, F. J. (2004) Therapeutic and diagnostic implications of Hsp90 activation. Trends Mol Med 10, 283–90.
Kamal, A., Thao, L., Sensintaffar, J., Zhang, L., Boehm, M. F., Fritz, L. C., and Burrows, F. J. (2003) A high affinity conformation of Hsp90 confers tumor selectivity on Hsp90 inhibitors. Nature 425, 407–410.
Kaur, G., Belotti, D., Burger, A. M., Fisher-Nielson, K., Borsotti, P., Riccardi, E., Thillainathan, J., Hollingshead, M., Sausville, E. A. and Giavazzi, R. (2004) Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: an orally bioavailable heat shock protein 90 modulator. Clin Cancer Res 10, 4813–21.
Koga, F., Xu, W., Karpova, T. S., McNally, J. G., Baron, R. and Neckers, L. (2006) Hsp90 inhibition transiently activates Src kinase and promotes Srcdependent Akt and Erk activation. Proc Natl Acad Sci U S A 103, 11318–22.
Kovacs, J. J., Murphy, P. J., Gaillard, S., Zhao, X., Wu, J. T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B. and Yao, T. P. (2005) HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 18, 601–7.
Lamb, J., Crawford, E. D., Peck, D., Modell, J. W., Blat, I. C., Wrobel, M. J., Lerner, J., Brunet, J. P., Subramanian, A., Ross, K. N., Reich, M., Hieronymus, H., Wei, G., Armstrong, S. A., Haggarty, S. J., Clemons, P. A., Wei, R., Carr, S. A., Lander, E. S. and Golub, T. R. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–35.
Lawson, B., Brewer, J. W. and Hendershot, L. M. (1998) Geldanamycin, an hsp90/GRP94-binding drug, induces increased transcription of endoplasmic reticulum (ER) chaperones via the ER stress pathway. J. Cell. Physiol.. 174, 170–8.
Lotz, G. P., Lin, H., Harst, A. and Obermann, W. M. (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, 17228–35.
Marcu, M. G., Chadli, A., Bouhouche, I., Catelli, M. and Neckers, L. M. (2000) The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the C-terminus of the chaperone. J. Biol. Chem. 275, 37181–37186.
Maroney, A. C., Marugan, J. J., Mezzasalma, T. M., Barnakov, A. N., Garrabrant, T. A., Weaner, L. E., Jones, W. J., Barnakova, L. A., Koblish, H. K., Todd, M. J., Masucci, J. A., Deckman, I. C., Galemmo, R. A., Jr. and Johnson, D. L. (2006) Dihydroquinone ansamycins: toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives. Biochemistry 45, 5678–85.
Marques, C., Guo, W., Pereira, P., Taylor, A., Patterson, C., Evans, P. C. and Shang, F. (2006) The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. Faseb J 20, 741–3.
McLaughlin, S. H., Sobott, F., Yao, Z. P., Zhang, W., Nielsen, P. R., Grossmann, J. G., Laue, E. D., Robinson, C. V. and Jackson, S. E. (2006) The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins. J Mol Biol 356, 746–58.
Meares, G. P., Zmijewska, A. A. and Jope, R. S. (2004) Heat shock protein-90 dampens and directs signaling stimulated by insulin-like growth factor-1 and insulin. FEBS Lett 574, 181–6.
Merlo, L. M., Pepper, J. W., Reid, B. J. and Maley, C. C. (2006) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6, 924–35.
Meyer, P., Prodromou, C., Liao, C., Hu, B., Mark Roe, S., Vaughan, C. K., Vlasic, I., Panaretou, B., Piper, P. W. and Pearl, L. H. (2004) Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. Embo J.
Mimnaugh, E. G., Xu, W., Vos, M., Yuan, X., Isaacs, J. S., Bisht, K. S., Gius, D. and Neckers, L. (2004) Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol Cancer Ther 3, 551–66.
Moore, S. K., Kozak, C., Robinson, E. A., Ullrich, S. J. and Appella, E. (1989) Murine 86- and 84-kDa heat shock proteins, cDNA sequences, chromosome assignments, and evolutionary origins. Journal of Biological Chemistry 264, 5343–51.
Mulholland, P. J., Ferry, D. R., Anderson, D., Hussain, S. A., Young, A. M., Cook, J. E., Hodgkin, E., Seymour, L. W. and Kerr, D. J. (2001) Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin. Ann. Oncol. 12, 245–8.
Muller, L., Schaupp, A., Walerych, D., Wegele, H. and Buchner, J. (2004) Hsp90 regulates the activity of wild type p53 under physiological and elevated temperatures. J Biol Chem 279, 48846–54.
Munster, P. N., Tong, W., Schwartz, L., Larson, S., Kenneson, K., De La Cruz, A., Rosen, N. and Scher, H. (2001) Phase 1 trial of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) in patients with advanced malignancies. Paper presented at the Proc. Am. Soc. Clin. Oncol., 2001.
Murtagh, J., Lu, H. and Schwartz, E. L. (2006) Taxotere-induced inhibition of human endothelial cell migration is a result of heat shock protein 90 degradation. Cancer Res 66, 8192–9.
Nanbu, K., Konishi, I., Mandai, M., Kuroda, H., Hamid, A. A., Komatsu, T. and Mori, T. (1998) Prognostic significance of heat shock proteins HSP70 and HSP90 in endometrial carcinomas. Cancer Detection & Prevention. 22, 549–55.
Nathan, D. F. and Lindquist, S. (1995) Mutational analysis of Hsp90 function: interactions with a steroid receptor and a protein kinase. Mol Cell Biol 15, 3917–25.
Nony, P., Gaude, H., Rossel, M., Fournier, L., Rouault, J. P. and Billaud, M. (2003) Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Oncogene 22, 9165–75.
Pearl, L. H. and Prodromou, C. (2000) Structure and in vivo function of Hsp90. Current Opinion in Structural Biology 10, 46–51.
Palermo, C.M., Westlake, C.A. and Gasiewicz, T.A. (2005) Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein. Biochemistry 44, 5041–5052.
Piper, P. W., Truman, A. W., Millson, S. H. and Nuttall, J. (2006) Hsp90 chaperone control over transcriptional regulation by the yeast Slt2(Mpk1)p and human ERK5 mitogen-activated protein kinases (MAPKs). Biochem Soc Trans 34, 783–5.
Plescia, J., Salz, W., Xia, F., Pennati, M., Zaffaroni, N., Daidone, M. G., Meli, M., Dohi, T., Fortugno, P., Nefedova, Y., Gabrilovich, D. I., Colombo, G. and Altieri, D. C. (2005) Rational design of shepherdin, a novel anticancer agent. Cancer Cell 7, 457–68.
Pratt, W. B. and Toft, D. O. (2003) Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) 228, 111–33.
Price, J. T., Quinn, J. M., Sims, N. A., Vieusseux, J., Waldeck, K., Docherty, S. E., Myers, D., Nakamura, A., Waltham, M. C., Gillespie, M. T. and Thompson, E. W. (2005) The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Cancer Res 65, 4929–38.
Prodromou, C., Siligardi, G., O’Brien, R., Woolfson, D. N., Regan, L., Panaretou, B., Ladbury, J. E., Piper, P. W. and Pearl, L. H. (1999) Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. Embo J 18, 754–62.
Queitsch, C., Sangster, T. A. and Lindquist, S. (2002) Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624.
Quraishi, H., Rush, S. J. and Brown, I. R. (1996) Expression of mRNA species encoding heat shock protein 90 (hsp90) in control and hyperthermic rabbit brain. J Neurosci Res 43, 335–45.
Ramanathan, A., Wang, C. and Schreiber, S. L. (2005a) Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci U S A 102, 5992–7.
Ramanathan, R. K., Trump, D. L., Eiseman, J. L., Belani, C. P., Agarwala, S. S., Zuhowski, E. G., Lan, J., Potter, D. M., Ivy, S. P., Ramalingam, S., Brufsky, A. M., Wong, M. K., Tutchko, S. and Egorin, M. J. (2005b) Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 11, 3385–91.
Richon, V. M. (2006) Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer 95 Suppl 1, S2–6.
Richter, K. and Buchner, J. (2006) hsp90: twist and fold. Cell 127, 251–3.
Roe, S. M., Prodromou, C., O’Brien, R., Ladbury, J. E., Piper, P. W. and Pearl, L. H. (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J. Med. Chem. 42, 260–266.
Ronnen, E. A., Kondagunta, G. V., Ishill, N., Sweeney, S. M., Deluca, J. K., Schwartz, L., Bacik, J. and Motzer, R. J. (2006) A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma. Invest New Drugs 24, 543–6.
Rosenhagen, M. C., Soti, C., Schmidt, U., Wochnik, G. M., Hartl, F. U., Holsboer, F., Young, J. C. and Rein, T. (2003) The heat shock protein 90-targeting drug cisplatin selectively inhibits steroid receptor activation. Mol Endocrinol 17, 1991–2001.
Rosser, M. F. and Nicchitta, C. V. (2000) Ligand interactions in the adenosine nucleotide-binding domain of the Hsp90 chaperone, GRP94. I. Evidence for allosteric regulation of ligand binding. J Biol Chem 275, 22798–805.
Ruden, D. M., Garfinkel, M. D., Sollars, V. E. and Lu, X. (2003) Waddington’s widget: Hsp90 and the inheritance of acquired characters. Semin Cell Dev Biol 14, 301–10.
Ruden, D. M., Xiao, L., Garfinkel, M. D. and Lu, X. (2005) Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer. Hum Mol Genet 14 Spec No 1, R149–55.
Rutherford, S. L. (2003) Between genotype and phenotype: protein chaperones and evolvability. Nat Rev Genet 4, 263–74.
Rutherford, S. L. and Lindquist, S. (1998) Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342.
Sanderson, S., Valenti, M., Gowan, S., Patterson, L., Ahmad, Z., Workman, P. and Eccles, S. A. (2006) Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis. Mol Cancer Ther 5, 522–32.
Sangster, T. A., Lindquist, S. and Queitsch, C. (2004) Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance. Bioessays 26, 348–62.
Schnur, R. C., Corman, M. L., Gallaschun, R. J., Cooper, B. A., Dee, M. F., Doty, J. L., Muzzi, M. L., Moyer, J. D., DiOrio, C. I., Barbacci, E. G. and et al. (1995) Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives. J. Med. Chem. 38, 3806–12.
Schulte, T. W., Akinaga, S., Murakata, T., Agatsuma, T., Sugimoto, S., Nakano, H., Lee, Y. S., Simen, B. B., Argon, Y., Felts, S., Toft, D. O., Neckers, L. M. and Sharma, S. V. (1999) Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones. Mol Endocrinol 13, 1435–48.
Sepehrnia, B., Paz, I. B., Dasgupta, G. and Momand, J. (1996) Heat shock protein 84 forms a complex with mutant p53 protein predominantly within a cytoplasmic compartment of the cell. J Biol Chem 271, 15084–15090.
Sharp, S. and Workman, P. (2006) Inhibitors of the HSP90 molecular chaperone: current status. Adv Cancer Res 95, 323–48.
Shaw, R. J., Bardeesy, N., Manning, B. D., Lopez, L., Kosmatka, M., DePinho, R. A. and Cantley, L. C. (2004a) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–9.
Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A. and Cantley, L. C. (2004b) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 101, 3329–35.
Shiau, A. K., Harris, S. F., Southworth, D. R. and Agard, D. A. (2006) Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell 127, 329–40.
Shinozaki, F., Minami, M., Chiba, T., Suzuki, M., Yoshimatsu, K., Ichikawa, Y., Terasawa, K., Emori, Y., Matsumoto, K., Kurosaki, T., Nakai, A., Tanaka, K. and Minami, Y. (2006) Depletion of hsp90beta induces multiple defects in B cell receptor signaling. J Biol Chem 281, 16361–9.
Sjoblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D., Leary, R. J., Ptak, J., Silliman, N., Szabo, S., Buckhaults, P., Farrell, C., Meeh, P., Markowitz, S. D., Willis, J., Dawson, D., Willson, J. K., Gazdar, A. F., Hartigan, J., Wu, L., Liu, C., Parmigiani, G., Park, B. H., Bachman, K. E., Papadopoulos, N., Vogelstein, B., Kinzler, K. W. and Velculescu, V. E. (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–74.
Smith, D. F., Whitesell, L., Nair, S. C., Chen, S., Prapapanich, V. and Rimerman, R. A. (1995) Progesterone receptor structure and function altered by geldanamycin, an hsp90-binding agent. Mol. Cell. Biol. 15, 6804–12.
Soga, S., Neckers, L. M., Schulte, T. W., Shiotsu, Y., Akasaka, K., Narumi, H., Agatsuma, T., Ikuina, Y., Murakata, C., Tamaoki, T. and Akinaga, S. (1999) KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res 59, 2931–2938.
Sollars, V., Lu, X., Xiao, L., Wang, X., Garfinkel, M. D. and Ruden, D. M. (2003) Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat Genet 33, 70–4.
Soti, C., Pal, C., Papp, B. and Csermely, P. (2005) Molecular chaperones as regulatory elements of cellular networks. Curr Opin Cell Biol 17, 210–215.
Soti, C., Racz, A. and Csermely, P. (2002) A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. J. Biol. Chem. 277, 7066–7075.
Soti, C., Vermes, A., Haystead, T. A. and 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, 2421–8.
Sreedhar, A. S., Kalmar, E., Csermely, P. and Shen, Y. F. (2004) Hsp90 isoforms: functions, expression and clinical importance. FEBS Lett 562, 11–5.
Stoler, D. L., Chen, N., Basik, M., Kahlenberg, M. S., Rodriguez-Bigas, M. A., Petrelli, N. J. and Anderson, G. R. (1999) The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc. Natl. Acad. Sci. USA 96, 15121–15126.
Sydor, J. R., Normant, E., Pien, C. S., Porter, J. R., Ge, J., Grenier, L., Pak, R. H., Ali, J. A., Dembski, M. S., Hudak, J., Patterson, J., Penders, C., Pink, M., Read, M. A., Sang, J., Woodward, C., Zhang, Y., Grayzel, D. S., Wright, J., Barrett, J. A., Palombella, V. J., Adams, J. and Tong, J. K. (2006) Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A 103, 17408–13.
Trieb, K., Gerth, R., Holzer, G., Grohs, J. G., Berger, P. and Kotz, R. (2000) Antibodies to heat shock protein 90 in osteosarcoma patients correlate with response to neoadjuvant chemotherapy. Br. J. Cancer 82, 85–7.
Vaughan, C. K., Gohlke, U., Sobott, F., Good, V. M., Ali, M. M., Prodromou, C., Robinson, C. V., Saibil, H. R. and Pearl, L. H. (2006) Structure of an Hsp90-Cdc37-Cdk4 complex. Mol Cell 23, 697–707.
Voss, A. K., Thomas, T. and Gruss, P. (2000) Mice lacking HSP90beta fail to develop a placental labyrinth. Development 127, 1–11.
Westerheide, S. D., Kawahara, T. L., Orton, K. and Morimoto, R. I. (2006) Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem 281, 9616–22.
Whitesell, L., Bagatell, R. and Falsey, R. (2003) The stress response: implications for the clinical development of hsp90 inhibitors. Curr Cancer Drug Targets 3, 349–58.
Whitesell, L. and Lindquist, S. L. (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5, 761–72.
Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E. and Neckers, L. M. (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc. Natl. Acad. Sci. USA 91, 83248.
Whitesell, L., Sutphin, P., An, W. G., Schulte, T., Blagosklonny, M. V. and Neckers, L. (1997) Geldanamycin-stmulated destabilization of mutated p53 is mediated by the proteasome in vivo. Oncogene 14, 2809–2816.
Xiao, H. and Lis, J. T. (1989) Heat shock and developmental regulation of the Drosophila melanogaster hsp83 gene. Mol Cell Biol 9, 1746–53.
Xu, W., Marcu, M., Yuan, X., Mimnaugh, E., Patterson, C. and Neckers, L. (2002) Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci U S A 99, 12847–52.
Xu, W., Yuan, X., Beebe, K., Xiang, Z. and Neckers, L. (2007) Loss of Hsp90 Association Up-Regulates Src-Dependent ErbB2 Activity. Mol Cell Biol 27, 220–8.
Xu, Y., Singer, M. A. and Lindquist, S. (1999) Maturation of the tyrosine kinase csrc as a kinase and as a substrate depends on the molecular chaperone Hsp90. Proc Natl Acad Sci U S A 96, 109–14.
Yorgin, P., Hartson, S., Fellah, A., Scroggins, B., Huang, W., Katsanis, E., Couchman, J., Matts, R. and Whitesell, L. (2000) Effects of geldanamycin, a heat-shock protein 90-binding agent, on T-cell function and T-cell nonreceptor protein tyrosine kinases. J. Immunol. 164, 2915–2923.
Yue, L., Karr, T. L., Nathan, D. F., Swift, H., Srinivasan, S. and Lindquist, S. (1999) Genetic analysis of viable Hsp90 alleles reveals a critical role in Drosophila spermatogenesis. Genetics 151, 1065–79.
Yun, B. G., Huang, W., Leach, N., Hartson, S. D. and Matts, R. L. (2004) Novobiocin induces a distinct conformation of Hsp90 and alters Hsp90-cochaperone-client interactions. Biochemistry 43, 8217–29.
Zhang, H., Yang, Y. C., Zhang, L., Fan, J., Chung, D., Choi, D., Grecko, R., Timony, G., Karjian, P., Boehm, M. and Burrows, F. (2006) Dimeric ansamycins-A new class of antitumor Hsp90 modulators with prolonged inhibitory activity. Int J Cancer.
Zhao, R., Davey, M., Hsu, Y. C., Kaplanek, P., Tong, A., Parsons, A. B., Krogan, N., Cagney, G., Mai, D., Greenblatt, J., Boone, C., Emili, A. and Houry, W. A. (2005) Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell 120, 715–27.
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Whitesell, L., McLellan, C.A. (2007). Targeting Hsp90 Function to Treat Cancer: Much More to Be Learned. In: Calderwood, S.K., Sherman, M.Y., Ciocca, D.R. (eds) Heat Shock Proteins in Cancer. Heat Shock Proteins, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6401-2_13
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