本論文以觀察膠達那黴素 (geldanamycin, GA) 引發大鼠腦瘤細胞 (RBT 9L cells) 的逆境反應為始，研究其對熱休克蛋白HSP90同源異構體 (isoforms) 表達的調控機制。膠達那黴素為袢霉素 (ansamycin) 所衍生之苯二酮 (benzoquinone) 化合物，原本由天然抗真菌活性的產物中分離而得到。其經由專一性競爭作用抑制熱休克蛋白HSP90之腺三磷酸合成脢 (ATPase) 活性，進而造成受HSP90保護之客戶蛋白質 (client proteins) 失活、不穩定而分解；這類蛋白質包括調節細胞生長、分化等為數眾多的訊息傳導蛋白，如蛋白質激酶，及固醇類荷爾蒙受體等。
近年來，許多報導已指出GA會引發熱休克反應，且以RBT 9L細胞為研究題材之文獻中，已知至少可引發HSP70、GRP78、GRP94等多種蛋白表現。在本研究中，我們觀察到低GA劑量誘發HSP90，僅一般處理劑量的十分之一。而HSP90在哺乳動物細胞中，皆存在兩種同源異構體：即HSP90α 與HSP90β，且不同層級的物種間都有極高的相似度。當改變電泳條件可成功分離HSP90α與β，並發現GA處理下之不同誘導規模。由分析蛋白質與RNA層次的誘導表現量，得知HSP90α誘導量大於HSP90β均有其一致性，故可推測GA誘導HSP90之不同表現量調控在基因層次。
為探討HSP90α 與HSP90β 基因層次的調控機制，我們依據 hsp90α 與 hsp90β 之啟動子基因序列，由其上分析得到多個可能的轉錄蛋白結合區域，進一步利用電泳凝膠遷移檢測法(Electrophoresis Mobility Shift Assay)，比較GA處理RBT 9L細胞之核蛋白與轉錄元(transcriptional elements)的結合情形。據此結果可以得知HSP90的誘導與熱休克因子HSF1對於HSE的結合有極大相關，且HSP90α 與 HSP90β序列上分布不同的HSE的結合情形也有所不同，並據此由兩組HSE之間找出各有一個相對重要的HSE；同時核蛋白在 hsp90α-HSE2 與hsp90β-HSE1的不同結合力也顯示了兩者誘導量不同的可能原因。另外，針對其他重要的基本轉錄元分析，則又發現核蛋白中對於GC-box (SP-1)的結合力也有所不同，可能與HSP90α的誘發規模比HSP90β高，以及HSP90β基礎表現量有關；而TATA-box上的結合力則可能顯示HSP90α誘導量會與TATA-box上結合的轉錄蛋白相關；另一方面，對於CRE的結合力則可能說明CRE上的轉錄蛋白與GA處理下對HSP90β的誘導作用有關。
綜言之，本研究發現GA的作用能透過HSF1對啟動子上特定HSE的結合來誘發HSP90，並對於兩種HSP90同源異構體在轉錄層次同樣具有重要的調控作用，這可能決定了它們的誘導量由基因層次乃至於蛋白質層次的顯著差異。

This thesis started by using geldanamycin (GA) to treat rat brain tumor (RBT) 9L cells. By observing cell stress response, we initiated the study of the differentially inductive mechanisms on heat shock protein 90 isoforms. Geldanamycin (GA) is an ansamycin-derivative benzoquinone compound, which was originally isolated as a natural product with anti-fungal activity. GA could inhibit the essential ATPase activity of HSP90 and results in inactivation, destabilization, and degradation of HSP90 client proteins, including a wide variety of signal-transducing proteins that regulate cell growth and differentiation, such as protein kinases and steroid hormone receptors.
But reports had shown that GA treatment could also induce heat-shock response; especially including HSP70, GRP78 and GRP94 in RBT 9L cells. In this study, we found only a 1/10 dose of GA (i.e., 0.5 贡M) could induce HSP90, compared to 5 贡M GA to induce those heat shock proteins like HSP70, GRP78 and GRP94. Furthermore, HSP90 exists two highly consistent isoforms, HSP90α and HSP90β, in mammalian cells. We further separated HSP90 isoforms by decrease pH (to 8.0) and percentage (9%) of PAGE gel; the results showed apparently differential induction of HSP90 isoforms through GA treatment (HSP90α > HSP90β). On the other hand, the consistencies were confirmed from RNA to protein level by real time qPCR analysis, Western Blotting and de novo synthetic analysis. Our results demonstrated that gene level regulation controlled the differential induction of HSP90 isoforms.
According to the promoter sequences of hsp90α and hsp90β, we evaluated the different importance of some transcriptional elements by Electrophoresis Mobility Shift Assay (EMSA). Interestingly, differential induction of HSP90α and β is related to the differential binding activities to HSEs in hsp90α and hsp90β promoters. In addition, we also observed the binding strengths on HSEs might imply how HSP90α is more inducible isoforms than HSP90β. On the other hand, the results of binding activities on basic transcription elements showed that GC-box (sp-1 site) involved in inductive level of HSP90α汹and HSP90β the binding on TATA-box and CRE were respectively related to the induction of HSP90α and HSP90β.
In conclusion, treatment with GA facilitate HSF1 binding to the distinct HSE sites on the promoters of hsp90α and hsp90β and further induce HSP90s. It agreed with the observations of differential induction on mRNA and protein level in 9L cells under treatment with GA.

Abravaya, K., Phillips, B. and Morimoto, R. I. (1991). "Heat shock-induced interactions of heat shock transcription factor and the human hsp70 promoter examined by in vivo footprinting." Mol Cell Biol 11(1): 586-92.
Ali, A., Bharadwaj, S., O'Carroll, R. and Ovsenek, N. (1998). "HSP90 interacts with and regulates the activity of heat shock factor 1 in Xenopus oocytes." Mol Cell Biol 18(9): 4949-60.
Amin, J., Ananthan, J. and Voellmy, R. (1988). "Key features of heat shock regulatory elements." Mol Cell Biol 8(9): 3761-9.
An, W. G., Schnur, R. C., Neckers, L. and Blagosklonny, M. V. (1997). "Depletion of p185erbB2, Raf-1 and mutant p53 proteins by geldanamycin derivatives correlates with antiproliferative activity." Cancer Chemother Pharmacol 40(1): 60-4.
Argon, Y. and Simen, B. B. (1999). "GRP94, an ER chaperone with protein and peptide binding properties." Semin Cell Dev Biol 10(5): 495-505.
Arrigo, A. P. (1998). "Small stress proteins: chaperones that act as regulators of intracel-lular redox state and programmed cell death." Biol Chem 379(1): 19-26.
Bagatell, R., Gore, L., Egorin, M. J., Ho, R., Heller, G., Boucher, N., Zuhowski, E. G., Whitlock, J. A., Hunger, S. P., Narendran, A., Katzenstein, H. M., Arceci, R. J., Boklan, J., Herzog, C. E., Whitesell, L., Ivy, S. P. and Trippett, T. M. (2007). "Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: a pediatric oncology experimental therapeutics investigators consortium study." Clin Cancer Res 13(6): 1783-8.
Bagatell, R., Paine-Murrieta, G. D., Taylor, C. W., Pulcini, E. J., Akinaga, S., Benjamin, I. J. and Whitesell, L. (2000). "Induction of a heat shock factor 1-dependent stress re-sponse alters the cytotoxic activity of hsp90-binding agents." Clin Cancer Res 6(8): 3312-8.
Baler, R., Dahl, G. and Voellmy, R. (1993). "Activation of human heat shock genes is ac-companied by oligomerization, modification, and rapid translocation of heat shock transcription factor HSF1." Mol Cell Biol 13(4): 2486-96.
Baler, R., Welch, W. J. and Voellmy, R. (1992). "Heat shock gene regulation by nascent polypeptides and denatured proteins: hsp70 as a potential autoregulatory factor." J Cell Biol 117(6): 1151-9.
Bertram, J., Palfner, K., Hiddemann, W. and Kneba, M. (1996). "Increase of P-glycoprotein-mediated drug resistance by hsp 90 beta." Anticancer Drugs 7(8): 838-45.
Bharadwaj, S., Ali, A. and Ovsenek, N. (1999). "Multiple components of the HSP90 cha-perone complex function in regulation of heat shock factor 1 In vivo." Mol Cell Biol 19(12): 8033-41.
Bienz, M. and Pelham, H. R. (1986). "Heat shock regulatory elements function as an in-ducible enhancer in the Xenopus hsp70 gene and when linked to a heterologous promoter." Cell 45(5): 753-60.
Brown, M. A., Zhu, L., Schmidt, C. and Tucker, P. W. (2007). "Hsp90--from signal trans-duction to cell transformation." Biochem Biophys Res Commun 363(2): 241-6.
Bruey, J. M., Ducasse, C., Bonniaud, P., Ravagnan, L., Susin, S. A., Diaz-Latoud, C., Gurbuxani, S., Arrigo, A. P., Kroemer, G., Solary, E. and Garrido, C. (2000). "Hsp27 negatively regulates cell death by interacting with cytochrome c." Nat Cell Biol 2(9): 645-52.
Cen, H., Zheng, S., Fang, Y. M., Tang, X. P. and Dong, Q. (2004). "Induction of HSF1 expression is associated with sporadic colorectal cancer." World J Gastroenterol 10(21): 3122-6.
Chang, Y. S., Lee, L. C., Sun, F. C., Chao, C. C., Fu, H. W. and Lai, Y. K. (2005). "In-volvement of calcium in the differential induction of heat shock protein 70 by heat shock protein 90 inhibitors, geldanamycin and radicicol, in human non-small cell lung cancer H460 cells." J Cell Biochem.
Chang, Y. S., Lo, C. W., Sun, F. C., Chang, M. D. and Lai, Y. K. (2006). "Differential ex-pression of Hsp90 isoforms in geldanamycin-treated 9L cells." Biochem Biophys Res Commun 344(1): 37-44.
Csermely, P., Schnaider, T., Soti, C., Prohaszka, Z. and Nardai, G. (1998). "The 90-kDa molecular chaperone family: structure, function, and clinical applications. A com-prehensive review." Pharmacol Ther 79(2): 129-68.
Cunniff, N. F., Wagner, J. and Morgan, W. D. (1991). "Modular recognition of 5-base-pair DNA sequence motifs by human heat shock transcription factor." Mol Cell Biol 11(7): 3504-14.
Dale, E. C., Yang, X., Moore, S. K. and Shyamala, G. (1996). "Cloning and characteriza-tion of the promoter for murine 84-kDa heat-shock protein." Gene 172(2): 279-84.
Dale, E. C., Yang, X., Moore, S. K. and Shyamala, G. (1997). "Murine 86-kDa heat shock protein gene and promoter." Cell Stress Chaperones 2(2): 87-93.
DeBoer, C., Meulman, P. A., Wnuk, R. J. and Peterson, D. H. (1970). "Geldanamycin, a new antibiotic." J Antibiot (Tokyo) 23(9): 442-7.
Ehrnsperger, M., Graber, S., Gaestel, M. and Buchner, J. (1997). "Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation." EMBO J 16(2): 221-9.
Erkine, A. M., Adams, C. C., Gao, M. and Gross, D. S. (1995). "Multiple protein-DNA interactions over the yeast HSC82 heat shock gene promoter." Nucleic Acids Res 23(10): 1822-9.
Farkas, T., Kutskova, Y. A. and Zimarino, V. (1998). "Intramolecular repression of mouse heat shock factor 1." Mol Cell Biol 18(2): 906-18.
Felts, S. J., Owen, B. A., Nguyen, P., Trepel, J., Donner, D. B. and Toft, D. O. (2000). "The hsp90-related protein TRAP1 is a mitochondrial protein with distinct func-tional properties." J Biol Chem 275(5): 3305-12.
Garrido, C. (2002). "Size matters: of the small HSP27 and its large oligomers." Cell Death Differ 9(5): 483-5.
Garrido, C., Fromentin, A., Bonnotte, B., Favre, N., Moutet, M., Arrigo, A. P., Mehlen, P. and Solary, E. (1998). "Heat shock protein 27 enhances the tumorigenicity of im-munogenic rat colon carcinoma cell clones." Cancer Res 58(23): 5495-9.
Garrido, C., Mehlen, P., Fromentin, A., Hammann, A., Assem, M., Arrigo, A. P. and Chauffert, B. (1996). "Inconstant association between 27-kDa heat-shock protein (Hsp27) content and doxorubicin resistance in human colon cancer cells. The dox-orubicin-protecting effect of Hsp27." Eur J Biochem 237(3): 653-9.
Giardina, C. and Lis, J. T. (1995). "Dynamic protein-DNA architecture of a yeast heat shock promoter." Mol Cell Biol 15(5): 2737-44.
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(8): 1169-76.
Goodson, M. L. and Sarge, K. D. (1995). "Heat-inducible DNA binding of purified heat shock transcription factor 1." J Biol Chem 270(6): 2447-50.
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(10): 8312-20.
Gupta, R. S. (1995). "Phylogenetic analysis of the 90 kD heat shock family of protein se-quences and an examination of the relationship among animals, plants, and fungi species." Mol Biol Evol 12(6): 1063-73.
Gurbuxani, S., Bruey, J. M., Fromentin, A., Larmonier, N., Parcellier, A., Jaattela, M., Martin, F., Solary, E. and Garrido, C. (2001). "Selective depletion of inducible HSP70 enhances immunogenicity of rat colon cancer cells." Oncogene 20(51): 7478-85.
Hansen, L. K., Houchins, J. P. and O'Leary, J. J. (1991). "Differential regulation of HSC70, HSP70, HSP90 alpha, and HSP90 beta mRNA expression by mitogen acti-vation and heat shock in human lymphocytes." Exp Cell Res 192(2): 587-96.
Harrison, C. J., Bohm, A. A. and Nelson, H. C. (1994). "Crystal structure of the DNA binding domain of the heat shock transcription factor." Science 263(5144): 224-7.
Hartl, F. U. (1996). "Molecular chaperones in cellular protein folding." Nature 381(6583): 571-9.
Hennighausen, L. and Lubon, H. (1987). "Interaction of protein with DNA in vitro." Me-thods Enzymol 152: 721-35.
Hickey, E., Brandon, S. E., Smale, G., Lloyd, D. and Weber, L. A. (1989). "Sequence and regulation of a gene encoding a human 89-kilodalton heat shock protein." Mol Cell Biol 9(6): 2615-26.
Jaattela, M. (1995). "Over-expression of hsp70 confers tumorigenicity to mouse fibrosar-coma cells." Int J Cancer 60(5): 689-93.
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(4): 317-27.
Jerome, V., Vourc'h, C., Baulieu, E. E. and Catelli, M. G. (1993). "Cell cycle regulation of the chicken hsp90 alpha expression." Exp Cell Res 205(1): 44-51.
Katschinski, D. M., Le, L., Heinrich, D., Wagner, K. F., Hofer, T., Schindler, S. G. and Wenger, R. H. (2002). "Heat induction of the unphosphorylated form of hypox-ia-inducible factor-1alpha is dependent on heat shock protein-90 activity." J Biol Chem 277(11): 9262-7.
Kawazoe, Y., Nakai, A., Tanabe, M. and Nagata, K. (1998). "Proteasome inhibition leads to the activation of all members of the heat-shock-factor family." Eur J Biochem 255(2): 356-62.
Kim, D., Kim, S. H. and Li, G. C. (1999). "Proteasome inhibitors MG132 and lactacystin hyperphosphorylate HSF1 and induce hsp70 and hsp27 expression." Biochem Bio-phys Res Commun 254(1): 264-8.
Kim, H. R., Kang, H. S. and Kim, H. D. (1999). "Geldanamycin induces heat shock pro-tein expression through activation of HSF1 in K562 erythroleukemic cells." IUBMB Life 48(4): 429-33.
Kingston, R. E., Schuetz, T. J. and Larin, Z. (1987). "Heat-inducible human factor that binds to a human hsp70 promoter." Mol Cell Biol 7(4): 1530-4.
Kumar, P., Ward, B. K., Minchin, R. F. and Ratajczak, T. (2001). "Regulation of the Hsp90-binding immunophilin, cyclophilin 40, is mediated by multiple sites for GA-binding protein (GABP)." Cell Stress Chaperones 6(1): 78-91.
Laemmli, U. K. (1970). "Cleavage of structural proteins during the assembly of the head of bacteriophage T4." Nature 227(5259): 680-5.
Lai, M. T., Huang, K. L., Chang, W. M. and Lai, Y. K. (2003). "Geldanamycin induction of grp78 requires activation of reactive oxygen species via ER stress responsive elements in 9L rat brain tumour cells." Cell Signal 15(6): 585-95.
Larson, J. S., Schuetz, T. J. and Kingston, R. E. (1988). "Activation in vitro of se-quence-specific DNA binding by a human regulatory factor." Nature 335(6188): 372-5.
Lindquist, S. and Craig, E. A. (1988). "The heat-shock proteins." Annu Rev Genet 22: 631-77.
Liu, X., Ye, L., Wang, J. and Fan, D. (1999). "Expression of heat shock protein 90 beta in human gastric cancer tissue and SGC7901/VCR of MDR-type gastric cancer cell line." Chin Med J (Engl) 112(12): 1133-7.
Livak, K. J. and Schmittgen, T. D. (2001). "Analysis of relative gene expression data us-ing real-time quantitative PCR and the 2(-Delta Delta C(T)) Method." Methods 25(4): 402-8.
Maloney, A. and Workman, P. (2002). "HSP90 as a new therapeutic target for cancer therapy: the story unfolds." Expert Opin Biol Ther 2(1): 3-24.
Mezger, V., Rallu, M., Morimoto, R. I., Morange, M. and Renard, J. P. (1994). "Heat shock factor 2-like activity in mouse blastocysts." Dev Biol 166(2): 819-22.
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 pro-motes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacu-olization, and enhances antitumor activity." Mol Cancer Ther 3(5): 551-66.
Minami, Y., Kawasaki, H., Miyata, Y., Suzuki, K. and Yahara, I. (1991). "Analysis of na-tive forms and isoform compositions of the mouse 90-kDa heat shock protein, HSP90." J Biol Chem 266(16): 10099-103.
Morimoto, R. I. (1993). "Cells in stress: transcriptional activation of heat shock genes." Science 259(5100): 1409-10.
Morimoto, R. I. (1998). "Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regula-tors." Genes Dev 12(24): 3788-96.
Morimoto, R. I., Kroeger, P. E. and Cotto, J. J. (1996). "The transcriptional regulation of heat shock genes: a plethora of heat shock factors and regulatory conditions." EXS 77: 139-63.
Nakai, A. and Morimoto, R. I. (1993). "Characterization of a novel chicken heat shock transcription factor, heat shock factor 3, suggests a new regulatory pathway." Mol Cell Biol 13(4): 1983-97.
Neckers, L. and Ivy, S. P. (2003). "Heat shock protein 90." Curr Opin Oncol 15(6): 419-24.
Neckers, L., Schulte, T. W. and Mimnaugh, E. (1999). "Geldanamycin as a potential an-ti-cancer agent: its molecular target and biochemical activity." Invest New Drugs 17(4): 361-73.
Nemoto, T., Ohara-Nemoto, Y., Ota, M., Takagi, T. and Yokoyama, K. (1995). "Mechan-ism of dimer formation of the 90-kDa heat-shock protein." Eur J Biochem 233(1): 1-8.
Nollen, E. A. and Morimoto, R. I. (2002). "Chaperoning signaling pathways: molecular chaperones as stress-sensing 'heat shock' proteins." J Cell Sci 115(Pt 14): 2809-16.
Pearl, L. H. and Prodromou, C. (2001). "Structure, function, and mechanism of the Hsp90 molecular chaperone." Adv Protein Chem 59: 157-86.
Pirkkala, L., Alastalo, T. P., Zuo, X., Benjamin, I. J. and Sistonen, L. (2000). "Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway." Mol Cell Biol 20(8): 2670-5.
Pirkkala, L., Nykanen, P. and Sistonen, L. (2001). "Roles of the heat shock transcription factors in regulation of the heat shock response and beyond." Faseb J 15(7): 1118-31.
Powers, M. V. and Workman, P. (2006). "Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors." Endocr Relat Cancer 13 Suppl 1: S125-35.
Pratt, W. B. and Toft, D. O. (2003). "Regulation of signaling protein function and traf-ficking by the hsp90/hsp70-based chaperone machinery." Exp Biol Med (Maywood) 228(2): 111-33.
Prodromou, C. and Pearl, L. H. (2003). "Structure and functional relationships of Hsp90." Curr Cancer Drug Targets 3(5): 301-23.
Rabindran, S. K., Giorgi, G., Clos, J. and Wu, C. (1991). "Molecular cloning and expres-sion of a human heat shock factor, HSF1." Proc Natl Acad Sci U S A 88(16): 6906-10.
Rabindran, S. K., Haroun, R. I., Clos, J., Wisniewski, J. and Wu, C. (1993). "Regulation of heat shock factor trimer formation: role of a conserved leucine zipper." Science 259(5092): 230-4.
Rabindran, S. K., Wisniewski, J., Li, L., Li, G. C. and Wu, C. (1994). "Interaction be-tween heat shock factor and hsp70 is insufficient to suppress induction of DNA-binding activity in vivo." Mol Cell Biol 14(10): 6552-60.
Ramanathan, R. K., Egorin, M. J., Eiseman, J. L., Ramalingam, S., Friedland, D., Agar-wala, S. S., Ivy, S. P., Potter, D. M., Chatta, G., Zuhowski, E. G., Stoller, R. G., Naret, C., Guo, J. and Belani, C. P. (2007). "Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory ad-vanced cancers." Clin Cancer Res 13(6): 1769-74.
Rebbe, N. F., Hickman, W. S., Ley, T. J., Stafford, D. W. and Hickman, S. (1989). "Nuc-leotide sequence and regulation of a human 90-kDa heat shock protein gene." J Biol Chem 264(25): 15006-11.
Ritossa, P. (1962). "[Problems of prophylactic vaccinations of infants.]." Riv Ist Sieroter Ital 37: 79-108.
Sarge, K. D., Murphy, S. P. and Morimoto, R. I. (1993). "Activation of heat shock gene transcription by heat shock factor 1 involves oligomerization, acquisition of DNA-binding activity, and nuclear localization and can occur in the absence of stress." Mol Cell Biol 13(3): 1392-407.
Sarge, K. D., Zimarino, V., Holm, K., Wu, C. and Morimoto, R. I. (1991). "Cloning and characterization of two mouse heat shock factors with distinct inducible and consti-tutive DNA-binding ability." Genes Dev 5(10): 1902-11.
Schmitt, E., Gehrmann, M., Brunet, M., Multhoff, G. and Garrido, C. (2007). "Intracellu-lar and extracellular functions of heat shock proteins: repercussions in cancer ther-apy." J Leukoc Biol 81(1): 15-27.
Schulte, T. W. and Neckers, L. M. (1998). "The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin." Cancer Chemother Pharmacol 42(4): 273-9.
Schweinfest, C. W., Graber, M. W., Henderson, K. W., Papas, T. S., Baron, P. L. and Wat-son, D. K. (1998). "Cloning and sequence analysis of Hsp89alpha DeltaN, a new member of theHsp90 gene family." Biochim Biophys Acta 1398(1): 18-24.
Shen, Y., Liu, J., Wang, X., Cheng, X., Wang, Y. and Wu, N. (1997). "Essential role of the first intron in the transcription of hsp90beta gene." FEBS Lett 413(1): 92-8.
Shu, C. W., Cheng, N. L., Chang, W. M., Tseng, T. L. and Lai, Y. K. (2005). "Transactiva-tion of hsp70-1/2 in geldanamycin-treated human non-small cell lung cancer H460 cells: involvement of intracellular calcium and protein kinase C." J Cell Biochem 94(6): 1199-209.
Sistonen, L., Sarge, K. D., Phillips, B., Abravaya, K. and Morimoto, R. I. (1992). "Acti-vation of heat shock factor 2 during hemin-induced differentiation of human eryt-hroleukemia cells." Mol Cell Biol 12(9): 4104-11.
Solit, D. B., Ivy, S. P., Kopil, C., Sikorski, R., Morris, M. J., Slovin, S. F., Kelly, W. K., DeLaCruz, A., Curley, T., Heller, G., Larson, S., Schwartz, L., Egorin, M. J., Rosen, N. and Scher, H. I. (2007). "Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer." Clin Cancer Res 13(6): 1775-82.
Sorger, P. K. (1991). "Heat shock factor and the heat shock response." Cell 65(3): 363-6.
Sreedhar, A. S. and Csermely, P. (2004). "Heat shock proteins in the regulation of apopto-sis: new strategies in tumor therapy: a comprehensive review." Pharmacol Ther 101(3): 227-57.
Sreedhar, A. S., Kalmar, E., Csermely, P. and Shen, Y. F. (2004). "Hsp90 isoforms: func-tions, expression and clinical importance." FEBS Lett 562(1-3): 11-5.
Sreedhar, A. S., Mihaly, K., Pato, B., Schnaider, T., Stetak, A., Kis-Petik, K., Fidy, J., Si-monics, T., Maraz, A. and Csermely, P. (2003). "Hsp90 inhibition accelerates cell lysis. Anti-Hsp90 ribozyme reveals a complex mechanism of Hsp90 inhibitors in-volving both superoxide- and Hsp90-dependent events." J Biol Chem 278(37): 35231-40.
Stavreva, D. A., Muller, W. G., Hager, G. L., Smith, C. L. and McNally, J. G. (2004). "Rapid glucocorticoid receptor exchange at a promoter is coupled to transcription and regulated by chaperones and proteasomes." Mol Cell Biol 24(7): 2682-97.
Sullivan, W. P. and Toft, D. O. (1993). "Mutational analysis of hsp90 binding to the progesterone receptor." J Biol Chem 268(27): 20373-9.
Sun, F. C., Wei, S., Li, C. W., Chang, Y. S., Chao, C. C. and Lai, Y. K. (2006). "Localiza-tion of GRP78 to mitochondria under the unfolded protein response." Biochem J 396(1): 31-9.
Supko, J. G., Hickman, R. L., Grever, M. R. and Malspeis, L. (1995). "Preclinical phar-macologic evaluation of geldanamycin as an antitumor agent." Cancer Chemother Pharmacol 36(4): 305-15.
Takayama, S., Reed, J. C. and Homma, S. (2003). "Heat-shock proteins as regulators of apoptosis." Oncogene 22(56): 9041-7.
Terasawa, K., Minami, M. and Minami, Y. (2005). "Constantly updated knowledge of Hsp90." J Biochem 137(4): 443-7.
Trinklein, N. D., Chen, W. C., Kingston, R. E. and Myers, R. M. (2004). "Transcriptional regulation and binding of heat shock factor 1 and heat shock factor 2 to 32 human heat shock genes during thermal stress and differentiation." Cell Stress Chaperones 9(1): 21-8.
Vuister, G. W., Kim, S. J., Orosz, A., Marquardt, J., Wu, C. and Bax, A. (1994). "Solution structure of the DNA-binding domain of Drosophila heat shock transcription fac-tor." Nat Struct Biol 1(9): 605-14.
Weigel, B. J., Blaney, S. M., Reid, J. M., Safgren, S. L., Bagatell, R., Kersey, J., Neglia, J. P., Ivy, S. P., Ingle, A. M., Whitesell, L., Gilbertson, R. J., Krailo, M., Ames, M. and Adamson, P. C. (2007). "A phase I study of 17-allylaminogeldanamycin in re-lapsed/refractory pediatric patients with solid tumors: a Children's Oncology Group study." Clin Cancer Res 13(6): 1789-93.
Weizsaecker, M., Deen, D. F., Rosenblum, M. L., Hoshino, T., Gutin, P. H. and Barker, M. (1981). "The 9L rat brain tumor: description and application of an animal model." J Neurol 224(3): 183-92.
Westwood, J. T., Clos, J. and Wu, C. (1991). "Stress-induced oligomerization and chro-mosomal relocalization of heat-shock factor." Nature 353(6347): 822-7.
Whitesell, L. and Lindquist, S. L. (2005). "HSP90 and the chaperoning of cancer." Nat Rev Cancer 5(10): 761-72.
Wu, C. (1984). "Two protein-binding sites in chromatin implicated in the activation of heat-shock genes." Nature 309(5965): 229-34.
Wu, C. (1995). "Heat shock transcription factors: structure and regulation." Annu Rev Cell Dev Biol 11: 441-69.
Wu, Y. P., Kita, K. and Suzuki, N. (2002). "Involvement of human heat shock protein 90 alpha in nicotine-induced apoptosis." Int J Cancer 100(1): 37-42.
Xiao, H. and Lis, J. T. (1988). "Germline transformation used to define key features of heat-shock response elements." Science 239(4844): 1139-42.
Yufu, Y., Nishimura, J. and Nawata, H. (1992). "High constitutive expression of heat shock protein 90 alpha in human acute leukemia cells." Leuk Res 16(6-7): 597-605.
Zhang, S. L., Yu, J., Cheng, X. K., Ding, L., Heng, F. Y., Wu, N. H. and Shen, Y. F. (1999). "Regulation of human hsp90alpha gene expression." FEBS Lett 444(1): 130-5.
Zhang, Y., Wang, J. S., Chen, L. L., Cheng, X. K., Heng, F. Y., Wu, N. H. and Shen, Y. F. (2004). "Repression of hsp90beta gene by p53 in UV irradiation-induced apoptosis of Jurkat cells." J Biol Chem 279(41): 42545-51.
Zou, J., Guo, Y., Guettouche, T., Smith, D. F. and 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): 471-80.
Zuo, J., Baler, R., Dahl, G. and Voellmy, R. (1994). "Activation of the DNA-binding abil-ity of human heat shock transcription factor 1 may involve the transition from an intramolecular to an intermolecular triple-stranded coiled-coil structure." Mol Cell Biol 14(11): 7557-68.