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Gene Review

HSP90AB1  -  heat shock protein 90kDa alpha (cytosolic)...

Homo sapiens

Synonyms: D6S182, HSP 84, HSP 90, HSP84, HSP90B, ...
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Disease relevance of HSP90AB1

  • Recombinant human HSP90 beta and recombinant yeast HSP90 as His6 constructs were also expressed in and purified from E. coli [1].
  • The most active compounds in the ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human colon cancer cells and the established molecular signature of Hsp90 inhibition, i.e., depletion of client proteins with upregulation of Hsp70 [2].
  • Expression of hsp90 and cyclin D1 in human breast cancer [3].
  • Shepherdin[79-83] abolished growth of AML xenograft tumors (mean of control group = 1698 mm3 and mean of treated group = 232 mm3; difference = 1466 mm3, 95% confidence interval = 505.8 to 2426; P = .008) without systemic or organ toxicity and inhibited Hsp90 function in vivo [4].
  • Apoptosis, Hsp90 client protein expression, and mitochondrial dysfunction were evaluated in AML types (myeloblastic, monocytic, and chronic myelogenous leukemia in blast crisis), patient-derived blasts, and normal mononuclear cells [4].

Psychiatry related information on HSP90AB1

  • The patients with 'high' levels of antibody to HSP70 showed higher initial Brief Psychiatric Rating Scale (BPRS) scores and showed greater clinical improvement than those with 'low' levels, while the patients with 'high' levels of antibody to HSP90 did not [5].

High impact information on HSP90AB1

  • Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell [6].
  • Hsp90 Cochaperone Aha1 Downregulation Rescues Misfolding of CFTR in Cystic Fibrosis [7].
  • In a novel in vitro system, in which human HSF1 can be activated by nonnative protein, heat, and geldanamycin, addition of Hsp90 inhibits activation [8].
  • We speculate that the inhibitory effect of the unliganded steroid binding domain may be mediated by heat shock protein hsp90, which binds selectively to the unliganded receptor [9].
  • These results suggest that dissociation of hsp90 and conversion to an inactive 4S intermediate could occur before the final event in ligand-mediated transactivation of gene expression [10].

Chemical compound and disease context of HSP90AB1

  • Our results indicate that inhibition of the hsp90-dependent trafficking mechanism prevents aggregation of the expanded glutamine androgen receptor, thereby opening a variety of novel therapeutic approaches to these neurodegenerative disorders [11].
  • The molecular chaperone hsp90 has emerged as an important therapeutic target in cancer and neurodegenerative diseases, including the polyglutamine expansion disorders, because of its ability to regulate the activity, turnover and trafficking of many proteins [11].
  • To address this, we examined whether the heat shock protein 90 (Hsp90) inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), would be efficacious in inhibiting breast cancer metastasis to bone [12].
  • Here, we examined the effect of the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) on doxorubicin-induced apoptosis in lymphoma [13].
  • We investigated the effects of cisplatin and the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination in a panel of human colon adenocarcinoma cell lines that differ in their p53 and mismatch repair status [14].

Biological context of HSP90AB1


Anatomical context of HSP90AB1

  • These findings suggest that HSP90 induces efficient activation of N-WASP downstream of phosphorylation signal by Src family kinases and is critical for N-WASP-dependent podosome formation and neurite extension [15].
  • Taxotere prevented the VEGF-induced phosphorylation of focal adhesion kinase, Akt, and endothelial nitric oxide synthase (eNOS), all of which are Hsp90 client proteins [20].
  • Here we present data that pan-PKC inhibitor GF109203X, but not classic PKC inhibitor Gö6976, specifically repressed heat shock-induced accumulation of mRNA as well as promoter activity of hsp90 beta, but not hsp90 alpha, in Jurkat cells [18].
  • On the other hand, the metal administration led to an increase of Hsp90 level in the cytosol, while the cytosolic levels of Hsp70 isoforms remained unaltered [21].
  • A CyP4O-associated protein was isolated from rabbit reticulocyte lysate by means of an affinity resin, and was identified as hsp90 [22].

Associations of HSP90AB1 with chemical compounds


Physical interactions of HSP90AB1

  • Heat shock induced conformational change of wild type p53 and binding to hsp90 [25].
  • Expression of mutant p53 prevents MDM2 from binding ARF and accumulating in the nucleolus in an hsp90-dependent fashion [26].
  • Here, we ask if wheat germ lysate also contains immunophilins of the FK506-binding class (FKBPs) that bind to the hsp90 component of the chaperone complex via tetratricopeptide repeat (TPR) domains [27].
  • In hypotonic cell extract (cytosol), unliganded progesterone receptor (PR) is known to form an oligomeric complex with heat shock protein 90 (hsp90), and this complex does not bind to DNA [28].
  • Treatment of cells with the hsp90 inhibitor geldanamycin inactivates steroid binding activity and increases the rate of GR turnover [29].

Enzymatic interactions of HSP90AB1

  • In addition, HSP90 protects phosphorylated and activated N-WASP from proteasome-dependent degradation, resulting in amplification of N-WASP-dependent actin polymerization [15].

Co-localisations of HSP90AB1

  • In AD brains, levels of HSP90 were increased in both the cytosolic and membranous fractions, and HSP90 was colocalized with amyloid plaques [30].

Regulatory relationships of HSP90AB1

  • Here, we show that heat shock protein 90 (HSP90) regulates N-WASP-induced actin polymerization in cooperation with phosphorylation of N-WASP [15].
  • Interactions between hsp90 and non-native beta-galactosidase neither lead to refolding nor stimulate hsp70- and hdj-1-dependent refolding [31].
  • In order to further elucidate the role of hsp90 in the endocrine response of cells, we have examined the effects of dexamethasone and RU38486 on the level of hsp90 mRNA in a system in which glucocorticoids down-regulate glucocorticoid receptor mRNA levels [32].
  • RACK1 activity is required for the mechanism of action for the HSP90 inhibitor 17-allylaminogeldanamycin to induce HIF-1alpha degradation [33].
  • HSF1 transactivation competence is repressed by an HSP90-containing multichaperone complex that interacts with trimeric factor [34].

Other interactions of HSP90AB1

  • Interaction of HSP90 to N-WASP leads to activation and protection from proteasome-dependent degradation [15].
  • The biological association of CyP-40 with hsp90 in many tissues may reflect a conjoint role in protein folding and trafficking [23].
  • Biochemical and genetic results suggest that HSP90, through its interaction with SGT1 (SUGT1), is required for kinetochore assembly [35].
  • These results suggest that the phosphorylations in the charged linker region of the HSP90 molecule modulate the formation of the functional cytosolic AhR complex [36].
  • Furthermore, time-course experiments revealed that transient treatment with 17-AAG between late S and G2/M phases causes substantial delocalization of CENP-H and CENP-I, a finding that strongly suggests that HSP90 participates in kinetochore assembly in a cell cycle-dependent manner [35].

Analytical, diagnostic and therapeutic context of HSP90AB1

  • The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG), which is currently in clinical trials, is thought to exert antitumor activity by simultaneously targeting several oncogenic signaling pathways [35].
  • Similar molecular alterations were induced by docetaxel plus trastuzumab combination, except for that there was a transient and complete disappearance of AR and HSP90 proteins 24 h after treatment [37].
  • The HSPs have thus become targets for rational anti-cancer drug design: HSP90 inhibitors are currently showing much promise in clinical trials, whereas the increased expression of HSPs in tumors is forming the basis of chaperone-based immunotherapy [38].
  • In homogenates of the same tissue samples that were used for immunohistochemistry, the PR was complexed with hsp90 [39].
  • Therefore, our results indicate that the high potency of GA in cell culture and in vivo can be accounted for by its time-dependent, tight binding to Hsp90 alone [40].


  1. Expression of recombinant human casein kinase II and recombinant heat shock protein 90 in Escherichia coli and characterization of their interactions. Shi, Y., Brown, E.D., Walsh, C.T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  2. Inhibition of hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Proisy, N., Sharp, S.Y., Boxall, K., Connelly, S., Roe, S.M., Prodromou, C., Slawin, A.M., Pearl, L.H., Workman, P., Moody, C.J. Chem. Biol. (2006) [Pubmed]
  3. Expression of hsp90 and cyclin D1 in human breast cancer. Yano, M., Naito, Z., Yokoyama, M., Shiraki, Y., Ishiwata, T., Inokuchi, M., Asano, G. Cancer Lett. (1999) [Pubmed]
  4. Antileukemic activity of shepherdin and molecular diversity of hsp90 inhibitors. Gyurkocza, B., Plescia, J., Raskett, C.M., Garlick, D.S., Lowry, P.A., Carter, B.Z., Andreeff, M., Meli, M., Colombo, G., Altieri, D.C. J. Natl. Cancer Inst. (2006) [Pubmed]
  5. Identification of antibodies to heat shock proteins 90 kDa and 70 kDa in patients with schizophrenia. Kim, J.J., Lee, S.J., Toh, K.Y., Lee, C.U., Lee, C., Paik, I.H. Schizophr. Res. (2001) [Pubmed]
  6. Structure and mechanism of the hsp90 molecular chaperone machinery. Pearl, L.H., Prodromou, C. Annu. Rev. Biochem. (2006) [Pubmed]
  7. Hsp90 Cochaperone Aha1 Downregulation Rescues Misfolding of CFTR in Cystic Fibrosis. Wang, X., Venable, J., Lapointe, P., Hutt, D.M., Koulov, A.V., Coppinger, J., Gurkan, C., Kellner, W., Matteson, J., Plutner, H., Riordan, J.R., Kelly, J.W., Yates, J.R., Balch, W.E. Cell (2006) [Pubmed]
  8. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Zou, J., Guo, Y., Guettouche, T., Smith, D.F., Voellmy, R. Cell (1998) [Pubmed]
  9. A movable and regulable inactivation function within the steroid binding domain of the glucocorticoid receptor. Picard, D., Salser, S.J., Yamamoto, K.R. Cell (1988) [Pubmed]
  10. Identification of a functional intermediate in receptor activation in progesterone-dependent cell-free transcription. Bagchi, M.K., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Nature (1990) [Pubmed]
  11. Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction. Thomas, M., Harrell, J.M., Morishima, Y., Peng, H.M., Pratt, W.B., Lieberman, A.P. Hum. Mol. Genet. (2006) [Pubmed]
  12. The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. 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., Thompson, E.W. Cancer Res. (2005) [Pubmed]
  13. Schedule-Dependent Synergy between the Heat Shock Protein 90 Inhibitor 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin and Doxorubicin Restores Apoptosis to p53-Mutant Lymphoma Cell Lines. Robles, A.I., Wright, M.H., Gandhi, B., Feis, S.S., Hanigan, C.L., Wiestner, A., Varticovski, L. Clin. Cancer Res. (2006) [Pubmed]
  14. Quantitative effects on c-Jun N-terminal protein kinase signaling determine synergistic interaction of cisplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines. Vasilevskaya, I.A., Rakitina, T.V., O'Dwyer, P.J. Mol. Pharmacol. (2004) [Pubmed]
  15. Interaction of HSP90 to N-WASP leads to activation and protection from proteasome-dependent degradation. Park, S.J., Suetsugu, S., Takenawa, T. EMBO J. (2005) [Pubmed]
  16. Sequence and regulation of a gene encoding a human 89-kilodalton heat shock protein. Hickey, E., Brandon, S.E., Smale, G., Lloyd, D., Weber, L.A. Mol. Cell. Biol. (1989) [Pubmed]
  17. Repression of hsp90beta gene by p53 in UV irradiation-induced apoptosis of Jurkat cells. Zhang, Y., Wang, J.S., Chen, L.L., Zhang, Y., Cheng, X.K., Heng, F.Y., Wu, N.H., Shen, Y.F. J. Biol. Chem. (2004) [Pubmed]
  18. PKC epsilon is a unique regulator for hsp90 beta gene in heat shock response. Wu, J.M., Xiao, L., Cheng, X.K., Cui, L.X., Wu, N.H., Shen, Y.F. J. Biol. Chem. (2003) [Pubmed]
  19. Nucleotide sequence and regulation of a human 90-kDa heat shock protein gene. Rebbe, N.F., Hickman, W.S., Ley, T.J., Stafford, D.W., Hickman, S. J. Biol. Chem. (1989) [Pubmed]
  20. Taxotere-induced inhibition of human endothelial cell migration is a result of heat shock protein 90 degradation. Murtagh, J., Lu, H., Schwartz, E.L. Cancer Res. (2006) [Pubmed]
  21. Interaction of rat renal glucocorticoid receptor with Hsp90 and Hsp70 upon stress provoked by mercury. Brkljacić, J., Perisić, T., Dundjerski, J., Matić, G. Journal of applied toxicology : JAT (2007) [Pubmed]
  22. Characterization of cyclophilin 40: highly conserved protein that directly associates with Hsp90. Yokoi, H., Kondo, H., Furuya, A., Hanai, N., Ikeda, J.E., Anazawa, H. Biol. Pharm. Bull. (1996) [Pubmed]
  23. Cyclophilin-40: evidence for a dimeric complex with hsp90. Hoffmann, K., Handschumacher, R.E. Biochem. J. (1995) [Pubmed]
  24. Transactivation of hsp70-1/2 in geldanamycin-treated human non-small cell lung cancer H460 cells: involvement of intracellular calcium and protein kinase C. Shu, C.W., Cheng, N.L., Chang, W.M., Tseng, T.L., Lai, Y.K. J. Cell. Biochem. (2005) [Pubmed]
  25. Phosphorylation and hsp90 binding mediate heat shock stabilization of p53. Wang, C., Chen, J. J. Biol. Chem. (2003) [Pubmed]
  26. Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. Peng, Y., Chen, L., Li, C., Lu, W., Chen, J. J. Biol. Chem. (2001) [Pubmed]
  27. Binding of immunophilins to the 90 kDa heat shock protein (hsp90) via a tetratricopeptide repeat domain is a conserved protein interaction in plants. Owens-Grillo, J.K., Stancato, L.F., Hoffmann, K., Pratt, W.B., Krishna, P. Biochemistry (1996) [Pubmed]
  28. Progesterone receptor and hsp90 are not complexed in intact nuclei. Pekki, A., Ylikomi, T., Syvälä, H., Tuohimaa, P. J. Steroid Biochem. Mol. Biol. (1994) [Pubmed]
  29. Neuronal nitric-oxide synthase is regulated by the Hsp90-based chaperone system in vivo. Bender, A.T., Silverstein, A.M., Demady, D.R., Kanelakis, K.C., Noguchi, S., Pratt, W.B., Osawa, Y. J. Biol. Chem. (1999) [Pubmed]
  30. Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. Kakimura, J., Kitamura, Y., Takata, K., Umeki, M., Suzuki, S., Shibagaki, K., Taniguchi, T., Nomura, Y., Gebicke-Haerter, P.J., Smith, M.A., Perry, G., Shimohama, S. FASEB J. (2002) [Pubmed]
  31. The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-1 have distinct roles in recognition of a non-native protein and protein refolding. Freeman, B.C., Morimoto, R.I. EMBO J. (1996) [Pubmed]
  32. Cloning and regulation by glucocorticoid receptor ligands of a rat hsp90. McGuire, J.A., Poellinger, L., Wikström, A.C., Gustafsson, J.A. J. Steroid Biochem. Mol. Biol. (1992) [Pubmed]
  33. RACK1 vs. HSP90: competition for HIF-1alpha degradation vs. stabilization. Liu, Y.V., Semenza, G.L. Cell Cycle (2007) [Pubmed]
  34. DAXX interacts with heat shock factor 1 during stress activation and enhances its transcriptional activity. Boellmann, F., Guettouche, T., Guo, Y., Fenna, M., Mnayer, L., Voellmy, R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  35. 17-AAG, an Hsp90 inhibitor, causes kinetochore defects: a novel mechanism by which 17-AAG inhibits cell proliferation. Niikura, Y., Ohta, S., Vandenbeldt, K.J., Abdulle, R., McEwen, B.F., Kitagawa, K. Oncogene (2006) [Pubmed]
  36. Phosphorylation analysis of 90 kDa heat shock protein within the cytosolic arylhydrocarbon receptor complex. Ogiso, H., Kagi, N., Matsumoto, E., Nishimoto, M., Arai, R., Shirouzu, M., Mimura, J., Fujii-Kuriyama, Y., Yokoyama, S. Biochemistry (2004) [Pubmed]
  37. Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms. Legrier, M.E., Oudard, S., Judde, J.G., Guyader, C., de Pinieux, G., Boyé, K., de Cremoux, P., Dutrillaux, B., Poupon, M.F. Br. J. Cancer (2007) [Pubmed]
  38. Heat shock proteins in cancer: chaperones of tumorigenesis. Calderwood, S.K., Khaleque, M.A., Sawyer, D.B., Ciocca, D.R. Trends Biochem. Sci. (2006) [Pubmed]
  39. Nuclear progesterone receptor is mainly heat shock protein 90-free in vivo. Tuohimaa, P., Pekki, A., Bläuer, M., Joensuu, T., Vilja, P., Ylikomi, T. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  40. A biochemical rationale for the anticancer effects of Hsp90 inhibitors: slow, tight binding inhibition by geldanamycin and its analogues. 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., Tummino, P.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
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