Sp1最初被定義為一個基本的轉錄因子，其會結合到目標基因啟動區上富含GC序列的區域進而活化目標基因的轉錄作用。近年來本實驗室的研究中已知Sp1會將c-Jun帶至12(S)-lipoxygenase基因的啟動區而此兩者間的交互作用對調控12(S)-lipoxygenase的基因表現扮演相當重要的角色；另一方面，已知Sp1會藉由將其他轉錄因子帶到基因啟動區而參予在許多不同基因的調控，例如: 持續表現、特殊組織表現以及調控細胞循環週期的基因等。於是，我們便有興趣去找出是否有其它會與Sp1有交互作用並且和調控12(S)-lipoxygenase的基因表現有關的蛋白質存在。首先我們利用蛋白質體分析方式欲篩選出會被Sp1複合物帶至啟動區的蛋白質，發現在二維電泳膠上面有許多蛋白質的表現而熱休克蛋白90alpha/beta為其中的兩個蛋白質。此外，透過GST-pull down、免疫沉澱及DNA affinity precipitation assay等分析方法也確認了熱休克蛋白90會與Sp1在離體之下有交互作用並且在A431細胞中能被Sp1帶到12(S)-lipoxygenase的基因啟動區上富含GC序列的區域上。再者，在熱休克蛋白90家族的專一性抑制劑Geldanamycin抑制熱休克蛋白90時，A431細胞中的12(S)-lipoxygenase其報告基因活性、mRNA及蛋白質表現都會明顯減少。另一方面，我們利用報告基因的分析欲找出在12(S)-lipoxygenase基因啟動區上是哪一區對熱休克蛋白90的作用是重要的，結果發現其上的Sp1結合位置是很重要的。
　　綜合上述的實驗結果，熱休克蛋白90會與Sp1有交互作用而被帶到12(S)-lipoxygenase的基因啟動區上進而在基因表現上扮演不可或缺的角色。

　Sp1 has been originally identified as a basic transcriptional factor, which binds to the GC-rich region of target gene’s promoter and then activates target gene’s transcription. In recent years, we have found that Sp1 will recruit c-Jun to the 12(S)-lipoxygenase promoter and this interaction plays an important role in regulating the 12(S)-lipoxygenase gene expression, in the other hand, Sp1 is implicated in the regulation of many different genes, such as housekeeping, tissue-specific and cell cycle-regulated genes by recruiting other transcriptional factors to the promoters of target genes. Therefore, we are interested in identifying other Sp1 interacting proteins, which involved in the regulation of 12(S)-lipoxygenase gene expression. First, we used the proteomic method to screen the candidate proteins, which could be recruited by the Sp1 complex. Several proteins were present in the 2D-gel, and two of these proteins were heat shock protein 90alpha/beta. Additionally, by using GST-pull down, immunoprecipitation assay and DNA Affinity Precipitation Assay (DAPA) also confirmed that Hsp90 could interact with Sp1 in vitro, and it is recruited to the promoter’s GC-rich region of 12(S)-lipoxygenase by Sp1 in A431 cells. Furthermore, when Hsp90 was inhibited by geldanamycin (GA), a specific inhibitor of Hsp90 family, the reporter activity, mRNA and protein level of 12(S)-lipoxygenase were reduced obviously in A431 cells. On the other hand, we used reporter assay to identify that which elements in the 12(S)-lipoxygenase gene promoter are important for Hsp90’s effect and found that Sp1 consensus sites were important.
　Taken these results together, Hsp90 could interact with Sp1 and be recruited to the promoter of 12(S)-lipoxygenase and then play an indispensable role in gene expression.

Akner, G., Mossberg, K., Sundqvist, K. G., Gustafsson, J. A., and Wikstrom, A. C. Evidence for reversible, non-microtubule and non-microfilament- dependent nuclear translocation of hsp90 after heat shock in human fibroblasts. Eur J Cell Biol. 58: 356-364, 1992.

Aligue, R., Akhavan-Niak, H., and Russell, P. Arole for hsp90 in cell cycle control: Wee1 tyrosine kinase activity requires interaction with hsp90. EMBO J. 13: 6099-6106, 1994.

Bamberger, C. M., Wald, A. M., Bamberger, H. M. Schulte. Inhibition of mineralocorticoid and glucocorticoid receptor function by the heat shock protein 90-binding agent geldanamycin. Mol. Cell. Endocrinol.131: 233-240, 1997.

Becker J., and Craig E. A. Heat-shock proteins as molecular chaperones. Eur. J. Biochem. 219: 11-23, 1994.

Beliakoff J., and Whitesell L. Hsp90: an emerging target for breast cancer therapy. Anticancer Drugs. 15: 651-662, 2004.

Bouchard, L., Lamarre, L., and Tremblay, P. J. Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell. 57: 931–940, 1989.

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

Bucci, M. F., Roviezzo, C., Cicala, W. C., and Sessa, G. Cirino. Geldanamycin, an inhibitor of heat shock protein 90 (hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo. Br. J. Pharmacol. 131: 13-16, 2000.

Buchner, J. Hsp90 & Co.- a folding for folding. Trends Biochem. Sci. 24: 136-141, 1999.

Capdevila, J., Yadagiri, P., Manna, S., and Faick, J. R. Absolute configuration of the hydroeicosatetraenoic acid (HETEs) formed during catalytic oxygenation of arachdonic acid by microsomal cytochrome p450. Biochem. Biophy. Res. Commun. 141: 10071-10110, 1986.

Caplan, A. J. Hsp90’s secrets unfold: new insights from structural and functional studies. Trends Cell Biol. 9: 262-268, 1999.

Caplan, A. J., Jackson, S., and Smith, D. Hsp90 reaches new heights. EMBO Rep. 4: 126-130, 2003.

Chang, W. C., Ning, C. C., Lin, M. T. & Huang, J. D. Epidermal growth factor enhances a microsomal 12-lipoxygenase activity in A431 cells. J. Biol. Chem. 267: 3657-3666, 1992.

Chavany, C., Mimnaugh, E., Mailler, P., Bitton, R., Nguyen, P., Trepel, J., Whitesell, L., Schnur, R., Moyer, J, D., and Neckers, L. p185(erbB2) binds to GRP94 in vivo-dissociation of the p185(erbB2)/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185(erbB2). J. Biol. Chem. 271: 4974-4977, 1996.

Chen, L. C., Chen, B. K., Liu, Y. W. & Chang, W. C. Induction of 12-lipoxygenase expression by transforming growth factor-alpha in human epidermoid carcinoma A431 cells. FEBS Lett. 455: 105-110, 1999.

Chen, B. K. & Chang, W. C. Functional interaction between c-Jun and prmoter factor Sp1 in epidermal growth factor-induced gene expression of human 12(S)-lipoxygenase. Proc. Natl. Acad. Sci. USA 97: 10406-10411, 2000.

Chiosis, G., Vilenchik, M., Kim, J., and Solit, D. Hsp90: the vulnerable chaperone. Drug Discov Today. 15: 881-888, 2004.

Chu, S., and Ferro, T. J. Sp1: Regulation of gene expression by phosphorylation. Gene. 348: 1-11, 2005.

Chupreta, S., Du, M., Todisco, A., Merchant, J.L. EGF stimulates gastrin promoter through activation of Sp1 kinase activity. Am. J. Physiol., Cell Physiol. 278: C697– C708, 2000.

Clark, J. D., Schievella, Ar., Nalefaski, E. A., and Lin, L. L. Cytosolic phospholipase A2. J. Lipid Mediat. Cell signal. 12: 83-117, 1995.

Csermely, P., Kajtar, J., Hollosi, M., Jalsovszky, G., Holly, S., Kahn, C. R., Gergely, P., Soti, C., Mihaly, K., and Somogyi, J. ATP induces a conformational change of the 90-kDa heat shock protein (hsp90). J. Biol. Chem. 268: 1901-1907, 1993.

Cutforth, T., and Rubin, G, M. Mutations in hsp83 and cdc37 impair signaling by the Sevenless receptor tyrosine kinase in Drosophila. Cell. 77: 1027-1036, 1994.

Czar, M. J., Galigniana, M. D., Silverstein, A. M., and Pratt, W. B. Geldanamycin, a heat shock protein 90-binding benzoquinone ansamycin, inhibits steroid-dependent translocation of the glucocorticoid receptor from the cytoplasm to the nucleus. Biochemistry. 36: 7776-7785, 1997.

Davies, T. H., Ning, Y. M., and Sanchez, E. R. A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J. Biol. Chem. 277: 4579-4600, 2002.

DeBoer, C., Meulman, P. A., Wnuk, R. J., and Peterson, D. H. Geldanamycin, a new antibiotic. J. Antibiot. (Tokyo) 23: 442-447, 1970.

Ellis, R. J. The general concept of molecular chaperones. Phil. Trans. R. Soc. Lond. 339B: 257-261, 1993.

Engels, F., and Nijkamp, F. P. Pharmacological inhibition of leukotriene actions. Pharm. World Sci. 20: 60-65, 1998.

Furstenberger, G., Hagedom, H., Jacobi, T., Besemelder, E., Stephan, M., Lehmann, W. D., and Marks, F. Characterization of an 8-lipoxygenase activity induced by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-
acetate in mouse skin in vivo. J. Biol. Chem. 266: 15738-15745, 1991.

Gasc, J. M., Renoir, J. M., Faber, L. F., Delahaye, F., and Baulien, F. F. Nuclear localization of two steroid receptor-associated proteins, hsp90 and p59. Exp Cell Res. 186: 362-367, 1990.

Georgopoulos, C., and Welch, W. J. Role of the major heat shock protein. Annu. Rev. Cell. Biol. 3: 601-634, 1993.

Grenert, J. P., Sullivan, W. P., Fadden, P., Haystead, T., Clark, J., Mimnaugh, E., Krutzsch, H., Ochel, H. J., Schulte, T. W., and Sausville, E. The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain tht regulates hsp90 conformation. J. Biol. Chem. 272: 23843-23850, 1997.

Grenert, J. P., Johnson, B. D., and Toft, D. O. The importance of ATP binding and hydrolysis by hsp90 in formation and function of protein heterocomplexes. J. Biol. Chem. 274: 17525-17533, 1999.

Hammarstom, S., Hamberg, M., Samuelsson, B., Duell, E. A., Stawiski, M., and Voorhees, J. J. Increased concentrations of nonesterified arachidonic acid, 12L-hydroxyl-5,8,10,14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis. Proc. Natl. Acad. Sci. USA 72: 5130-5134, 1975.

Hartson, S, D., and Matts, R, L. Association of hsp90 with cellular Src-family kinases in a cell-free system correlates with altered kinase structure and function. Biochemistry. 33: 8912-8920, 1994.

Hernandez, M. P., Sullivan, W. P., and Toft, D. O. The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone
complex. J. Biol. Chem. 277: 38294-38304, 2002.

Helmbrecht, K., Zeise, E., and Rensing, L. Chaperones in cell cycle regulation and mitogenic signal transduction: a review. Cell Prolif. 33: 341-365, 2000.

Hunter, T., and Pines, J. Cyclins and cancer II: cyclin D and CDK inhibitors come of age. Cell. 79: 573–582, 1994.

Hussain, H., Shornick, L. P., Shannon, V. R., Wilson, J. D., Funk, C. D., Pentland, A. P., and Holtzman, M. J. Epidermis contains platelet-type 12-
lipoxygenase that is overexpressed in germinal layer keratinocytes in psoriasis. Am. J. Physiol. 266: C243-C253, 1994.

Isaacs, J. T., and Coffey, D. S. Androgenic control of prostatic growth: regulation of steroid levels. UICC Monograph (Prostatic Cancer) 48:112–122, 1979.

Isaacs, J. S., Xu, W., and Neckers, L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell. 3: 213-217, 2003.

Iwama, G. K., Thomas, P. T., Forsyth, R. B., and Vijayan, M. M. Heat shock protein expression in fish. Rev. Fish Biol. Fisheri. 8: 35-56, 1998.
Iwama, G. K., Vijayan, M. M., Forsyth, R. B., and Ackerman, P. A. Heat shock proteins and physiological stress in fish. Am. Zool. 39: 901–909, 1999.
Jackson, S. P., MacDonald, J. J., Lees-Miller, S., Tjian, R. GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell. 63: 155– 165, 1990.

Jacob, U., and Buchner, J. Assisting spontaneity: the role of Hsp90 and small Hsps as molecular chaperones. Science. 19: 205-211, 1994.

Jolly C., and Morimoto R. I. Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J. Natl. Cancer Inst. 92: 1564-1573, 2000.

June, C. H., Fletcher, M. C., Ledbetter, J. A., Schieven, G. L., Siegel, J. N., Phillips, A. F., and Samelson, L. E. Inhibition of tyrosine phosphorylation prevents T-cell receptor–mediated signal transduction. Proc. Natl. Acad. Sci. USA 87: 7722–7726, 1990.

Kamal, A., Boehm, M. F., and Burrows, F. J. Therapeutic and diagnostic implications of Hsp90 activation. Trends Mol Med. 10: 283-290, 2004.

Kang, K. I., Meng, X. J., Devin-Leclerc, I., Bouhouche, A., Chadli, F., Cadepond, E. E. Baulieu, M. G., and Catelli. The molecular chaperone Hsp90 can negatively regulate the activity of a glucocorticosteroid-dependent promoter. Proc. Natl. Acad. Sci. USA 96: 1439-1444, 1999.

Kiang J. G., and Tsokos G. C. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol. Ther. 80: 183-201, 1998.

Krone, P. H., Sass, J. B., Lele, Z. Heat shock protein gene expression during embryonic development of the zebrafish. Cell. Mol. Life Sci. 53: 122-129, 1997b.

Lan, C., Lee, H. C., Tang, S., and Zhang, L. A novel mode of chaperone action. J. Biol. Chem. 279: 27607-27612, 2004.

Latchman, D. S. Heat shock proteins and cardiac protection. Cardiovasc. Res. 51: 637-646, 2001.

Liaw, Y. W., Liu, Y. W., Chen, B. K., & Chang, W. C. Induction of 12-lipoxygenase expression by phorbol 12-myristate 13-acetate in human epidermoid carcinoma A431 cells. Biochim. Biophys. Acta. 1389: 23-33, 1998.

Lin, L. L., A. Y., and Knopf, J. L. Cytosolic phospholipids A2 is coupled to hormonally regulated release of arachidonic acid. Proc. Natl. Acad. Sci. USA. 89: 6149-6151, 1992.

Lindquist, S., and Craig, E. A. The heat shock proteins. Annu. Rev. Genet. 22:
631-677, 1988.

Liu, Y. W., Asaoka, Y., Suzuki, H., Yoshimoto, T., Yamamoto, S. & Chang, W. C. Induction of 12-lipoxygenase expression by epidermal growth factor is mediated by protein kinase C in A431 cells. J. Pharmacol. Exp. Ther. 271: 567-573, 1994.

Maloney, A., Clarke, P. A., and Workman, P. Genes and Proteins Governing the Cellular Sensitivity to HSP90 Inhibitors: A Mechanistic Perspective. Current Cancer Drug Targets. 3: 331-341, 2003.

Mayer, M. P., and Bukau, B. The busy life of Hsp90. Curr Biol. 9: R322-R325, 1999.

McLaughlin, S. H., Smith, H. W., and Jackson, S. E. Stimulation of the Weak ATPase Activity of Human Hsp90 by a Client Protein. J. Mol. Biol. 315: 787-
798, 2002.

Mehta, T. A., Greenman, J., Ettelaie, C., Venkatasubramaniam, A., Chetten, I. C., and McCollum, P. T. Heat Shock Proteins in Vascular Disease—A Review. Eur J Vasc Endovasc Surg. 29: 395–402, 2005.

Milanini-Mongiat, J., Pouyssegur, J., and Pages, G. Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J. Biol. Chem. 277: 20631– 20639, 2002.

Miller, P., DiOrio, C., Moyer, M., Schnur, R. C., Bruskin, A., Cullen, W., and Moyer, J. D. Depletion of the erbB-2 gene product p185 by benzoquinoid ansamycins. Cancer Res. 54: 2724–2730, 1994.

Miyamoto, T., Ogino, N., Yamamoto, S., and Hayaishi, O. Purification of prostaglandin endoperoxide synthase from bovine vesicular gland microsomes. J. Biol. Chem. 251: 2629-2636, 1976.

Morrison D. K., and Cutler R. E. The complexity of Raf-1 regulation. Curr Opin Cell Biol. 9: 174-9, 1997.

Mosser D. D., and Morimoto R. I. Molecular chaperones and the stress of oncogenesis. Oncogene. 23: 2907-2918, 2004.

Murakami, Y., Mizuno, S., and Uehara, Y. Accelerated degradation of 160 kDa epidermal growth factor (EGF) receptor precursor by the tyrosine kinase inhibitor herbimycin A in the endoplasmic of A431 human epidermoid carcinoma cells. Biochem. J. 301: 63–68, 1994.

Murphy, P. J., Galignian, M. D., Morishima, Y., Harrell, J. M., Kwok, R. R., Ljungman, M., and Pratt, W. B. Pifithrin-α inhibits p53 signaling after interaction of the tumor suppressor protein with hsp90 and its nuclear translocation. J. Biol. Chem. 279: 30195-30201, 2004.

Nair, S. C., Toran, E. J., Rimerman, R. A., Hjermstad, S., Smithgall, T. E., and Smith, D. F. A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor. Cell Stress and Chaperones 1: 237–250, 1996.

Narumiya, S., Salomn, J. A., Cottee, F. H., Weatherley, B. C., and Flower, R. T. Arachidonic acid 15-lipoxygenase from rabbit peritoneal polymorphonuclear leukocytes. Partial purification and properties. J. Biol. Chem. 256: 9583-9592, 1981.

Nathan, D.F., and Lindquist, S. Mutational analysis of Hsp90 function: interactions with a steroid receptor and a protein kinase. Mol. Cell. Biol. 15: 3917-3925, 1995.

Neckers, L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med. 8: S55-S61, 2002.

Neckers, L., Schulte, T. W., and Mimnaugh, E. Geldanamycin as a potential anti-cancer agent: Its molecular target and biochemical activity. Invest New Drugs. 17: 361-373, 1999.

Ochel, H. J., Eichhorn, K., and Gademann, G. Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones. Cell Stress and Chaperones. 6: 105-112, 2001.

Omura, S., Iwai, Y., Takahashi, Y., Sadakane, N., Nakagawa, A., Oiwa, H., Hasegawa, Y., and Ikai, T. Herbimycin, a new antibiotic produced by a strain of streptomyces. J. Antibiot. (Tokyo) 32: 255-261, 1979.

Ono, Y., Kozai, Y., and Ootsu, K. Antitumor and cytocidal activities of a newly isolated benzenoid ansamycin, macbecin I. Gann. 73: 938-944, 1982.

Osborne, C. K., Yochmowitz, M. G., Knight, W. A., and McGuire, W. L.The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer. 46: 2884–2888, 1980.

Pandey, P., Saleh, A., Nakazawa, A., Kumar, S., Srinuvasula, S. M., Kumar, V., Weichselbaum, E., Nalin, C., Alnemri, E. S., Kufe, D., and Kharbanda, S. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J. 19: 4310-4322, 2000

Pearl L. H., and Prodromou C. Structure and in vivo function of Hsp90. Curr Cancer Drug Targets. 3: 301-23, 2003.

Piomelli, D., Volterra, A., Dale, N., Siegelbaum, S. A., Kandel, E. R., Schwartz, J. H., and Belardetti, F. Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature. 328: 38-43, 1987.

Pratt, W. B. The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol. 37: 297-326, 1997.

Pratt, W. B., and Welsh, M. J. Chaperone functions of the heat shock proteins associated with steroid receptors. Semin. Cell. Biol. 5: 83-93, 1994.

Rafty, L. A., Khachigian, L. M. Sp1 phosphorylation regulates inducible expression of platelet-derived growth factor B-chain gene via atypical protein kinase C-zeta. Nucleic Acids Res. 29: 1027– 1033, 2001.

Renoir, J. M., Buchou, T., and Baulieu, E. E. Involvement of a nonhormone-
binding 90-kilodalton protein in the nontransformed 8S form of the rabbit iteris progesterone receptor. Biochemistry. 25: 6405-6413, 1986.

Richter, K., and Buchner, J. Hsp90: chaperoning signal transduction. J Cell Physiol. 188: 281-290, 2001.
Roe, S. M., Prodromou, C., O’Brien, R., Ladbury, J. E., Piper, P. W., and Pearl, L. H. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem. 42: 260-266, 1999.

Rohlff, C., Ahmad, S., Borellini, F., Lei, J., Glazer, R. I. Modulation of transcription factor Sp1 by cAMP-dependent protein kinase. J. Biol. Chem. 272: 21137–21141, 1997.

Ryan, J. A., and Hightower, L. E. Stress proyeins as molecular biomarkers for environmental toxicology. Exs. 77: 411-424, 1996.

Sanchez, E. R., Housley, P., and Pratt, W. B. The molybdate-stabilized glucocorticoid binding complex of L-cells contains a 98-100 kdalton nonsteroid-binding phosphoproteon that is part of the murine heat-shock complex. J. Steroid Biochem. 24: 9-18, 1986.

Sanchez, E., Meshinchi, S., Tienrungroj, W., Schlesinger, M. J., Toft, D. O., and Pratt, W. B. Relationship of the 90-kDa murine heat-shock protein to the untransformed and transformed states of the L cell glucocorticoid receptor.
J. Biol. Chem. 262: 6986-6991, 1987.

Sarto, C., Binz, P. A., and Mocarelli, P. Heat shock proteins in human cancer. Electrophoresis 21: 1218-1226, 2000.

Sathiyaa, R., Campbell, T., and Vijayan, M. M. Cortisol modulates Hsp90 mRNA expression in primary cultures of trout hepatocytes. Comp. Biochem. Physiol. 129B: 679-685, 2001.

Schafer, D., Hamm-Kunzelmann, B., and Brand, K. Glucose regulates the promoter activity of aldolase A and pyruvate kinase M2 via dephosphorylation of Sp1. FEBS Lett. 417: 325–328, 1997.

Scheibel, T., and Buchner, J. The Hsp90 Complex—A Super-Chaperone machine as a Novel Drug Target. Biochemical Pharmacology. 56: 675–682, 1998.

Schneider, C., Sepp-Lorenzino, L., Nimmesgern, E., Ouerfelli, O., Danishefsky S., Rosen, N., and Hartl, F. U. Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90. Proc. Natl. Acad. Sci. U S A. 93: 14536-41, 1996.

Schulte, T. W., Blagosklonny, M. V., Ingui, C., and Neckers, L. Disruption of the Raf-1–Hsp90 molecularcomplex results in destabilization of Raf-1 and loss of Raf-1–Ras association. J. Biol. Chem. 270: 24585–24588, 1995.

Sekiya, F., Takagi, J., Usui, T., Kawajiri, K., Kobayashi, Y., Sata, F., and Saito, Y. 12(S)-Hydroxyeicosatetraenoic acid play a central role in the regulation of platelet activation. Biochem. Biophys Res. Commun. 179: 345-351, 1991.

Sliverstein, A. M., Galigniana, M. D., Chen, M. S., Owens-Grillo, J. K., Chinkers, M., and Pratt, W. B. Protein phosphatase 5 is a major component of glucocorticoid receptor. Hsp90 complexes with properties of an FK506-
binding immunophilin. J. Biol. Chem. 272: 16224-16230, 1997.

Smith, D. F., Sullivan, W, P., Marion, T, N., Zaitsu, K., Madden, B., McCormick, D, J., and Toft, D, O. Identification of a 60-kilodalton stress-
related protein, p60, which interacts with hsp90 and hsp70. Mol Cell Biol. 13: 869-76, 1993.

Smith, T. R., Tremblay, G. C., and Bradley, T. M. Hsp70 and a 54 kDa protein (Osp54) are induced in Salmon (Salmo salar) in response to hyperosmotic stress. J. Exp. Zool. 284: 286-298, 1999.

Smith, D. F., Whitesell, L., and Katsanis, E. Molecular chaperones: biology and prospects for pharmacological intervention. Pharmacol Rev. 50: 493-514,
1998.

Smith, D. F., Whitesell, L., Nair, S. C., Chen, S. Y., Prapapanich, V., and Rimerman, R. A. Progesterone receptor structure and function altered by geldanamycin, an hsp90-binding agent. Mol. Cell. Biol. 15: 6804–6812, 1995.

Sreedhar, A. S., Kalmar, E., Csermely, P., and Shen, Y. F. Hsp90 isoforms: functions, expression and clinical importance. FEBS Letters. 562: 11-15, 2004.

Sreedhar, A. S., Soti, C., Csermely, P. Inhibition of Hsp90: a new strategy for inhibiting protein kinases. Biochim Biophys Acta. 1697: 233-242, 2004.

Stebbins, C. E., Russo, A. A., Schneider, C., Rosen, N., Hartl, F. U., and Pavletich, N. P. Crystal structure of an Hsp90-Geldanamycin complex: Targeting of a protein chaperone by an antitunor agent. Cell. 89: 239-250, 1997.

Stancato, L, F., Chow, Y, H., Hutchison, K. A., Perdew, G, H., Jove, R., and Pratt, W, B. Raf exists in a native heterocomplex with hsp90 and p50 that can be reconstituted in a cell-free system. J. Biol. Chem. 268: 21711-21716, 1993.

Stepanova, L., Leng, X., Parker, S, B., and Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10: 1491-1502, 1996.

Tang, D. G., and Honn, K. V. 12-Lipoxygenase, 12(S)-HETE, and cancer metastasis. Ann. N. Y. Acad. Sci. 744: 199-215, 1994.

Tang, D. G., Chen, Y. Q., and Honn, K. V. Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. Proc. Natl. Acad. Sci. USA 93: 5241-5246, 1996.

Thompson, C. B., Dorup, I., Ahn, J. P., Leong, K. K., and McDonough, A. A. Glucocorticoids increase sodium pump alpha2- and beta1-subunit abundance and mRNA in rat skeletal muscle. Am. J. Physiol. 280: C509-C516, 2001

Uehara, Y. Natural product origins of Hsp90 inhibitors. Current Cancer Drug Targets. 3: 325-330 325, 2003.

Van Leyen, K., Duvosisn, R. M., Engelhardt, H., and Wiedmann, M. A function for lipoxygenase in programmed organrlle degradation. Nature 395: 392-395, 1990.

Welch, W. J. Heat shock proteins functioning as molecular chaperones: their roles in normal and stress cells. Philos. Trans. R. Soc. Lond. 339B: 327-333, 1993.

Whitesell, L., and Cook, P. Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells. Mol. Endocrinol. 10: 705-712, 1996.

Whitelaw, M, L., Hutchison, K., and Perdew, G. H. A 50-kDa cytosolic protein complexed with the 90-kDa heat shock protein(hsp90) is the same protein complexed with pp60v-src hsp90 in cells transformed by the Rous sarcoma virus. J. Biol. Chem. 266: 16436-16440, 1991.

Winitiz, S., Gupta, S. K., Cian, N., Heasley, L. E., Nemenoff, R. A., and Johnson, G. L. Expression of Gi2α subunit inhibits ATP and thrombin stimulation of cytoplasmic phospholipase A2-mediated arachidonic acid release independent of Ca++ and mitogen-activated protein. J. Biol. Chem. 269: 1889-1895, 1994.

Workman, A. Altered states: selectively drugging the Hsp90 cancer chaperone. Trends Mol Med. 10: 47-51, 2004.

Workman, P. Overview: translaying Hsp90 biology into Hsp90 drugs.
Current Cancer Drug Targets. 3: 297-300, 2003.

Xu, Y., and Lindquist, S. Heat-shock protein hsp90 governs the activity of pp60v-src kinase. Proc. Natl. Acad. Sci. USA. 90: 7074-7078, 1993.

Xu, X. X., Rock, C. O., Qin, Z., Leslie, C. C., and Jackowski, S. Regulation of cytosolic phospholipase A2 phosphorylation and eicosanoid production by colony-stimulating factor. J. Biol. Chem. 269: 31693-31700, 1994.

Yamamoto, S. Mammalian lipoxygenase: molecular structures and functions. Biochim. Biophys. Acta. 1128: 117-131, 1992.

Yang, X. D., and Feige, U. Heat shock proteins in autoimmuno disease. From causative antigen to specific therapy ? Experientia. 48: 650-656, 1992.

Yoshimoto, T., Arakawa, T., Hada, T., Yamamoto, S. & Takahashi, E. Structure and chromosomal localization of human arachidonate 12-lipoxygenase gene. J. Biol. Chem. 267: 24805-24809, 1992.

Young, J. C., Agashe, V. R., Siegers, K., and Hartl, F. U. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol. 5: 781-791, 2004.