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      Therapeutic and diagnostic implications of Hsp90 activation

      review-article
      1 , 2 , 1
      Trends in Molecular Medicine
      Elsevier Ltd.

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          Abstract

          The molecular chaperone heat-shock protein 90 (Hsp90) is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. Hsp90 inhibition results in the proteasomal degradation of these client proteins and leads to potent antitumor activity. The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is presently in clinical trials. Recent work has identified the role of Hsp90 in multiple signal transduction pathways and revealed that the molecular mechanism of tumor selectivity by Hsp90 inhibitors is the result of an activated, high-affinity conformation of Hsp90 in tumors. This review discusses these recent advances in the understanding of tumor Hsp90 for the treatment and diagnosis of cancer. In addition, the role of Hsp90 in non-oncological diseases will also be discussed.

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          Most cited references61

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          Cellular survival: a play in three Akts.

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            A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors.

            Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signalling proteins, including HER-2/ErbB2, Akt, Raf-1, Bcr-Abl and mutated p53. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells compared to normal cells, and the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is currently in phase I clinical trials. However, the molecular basis of the tumour selectivity of Hsp90 inhibitors is unknown. Here we report that Hsp90 derived from tumour cells has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells. Tumour Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics.
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              Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1.

              Heat shock and other proteotoxic stresses cause accumulation of nonnative proteins that trigger activation of heat shock protein (Hsp) genes. A chaperone/Hsp functioning as repressor of heat shock transcription factor (HSF) could make activation of hsp genes dependent on protein unfolding. In a novel in vitro system, in which human HSF1 can be activated by nonnative protein, heat, and geldanamycin, addition of Hsp90 inhibits activation. Reduction of the level of Hsp90 but not of Hsp/c70, Hop, Hip, p23, CyP40, or Hsp40 dramatically activates HSF1. In vivo, geldanamycin activates HSF1 under conditions in which it is an Hsp90-specific reagent. Hsp90-containing HSF1 complex is present in the unstressed cell and dissociates during stress. We conclude that Hsp90, by itself and/or associated with multichaperone complexes, is a major repressor of HSF1.
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                Author and article information

                Contributors
                Journal
                Trends Mol Med
                Trends Mol Med
                Trends in Molecular Medicine
                Elsevier Ltd.
                1471-4914
                1471-499X
                12 May 2004
                1 June 2004
                12 May 2004
                : 10
                : 6
                : 283-290
                Affiliations
                [1 ]Department of Biology, Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, CA 92121, USA
                [2 ]Department of Medicinal Chemistry, Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, CA 92121, USA
                Article
                S1471-4914(04)00103-0
                10.1016/j.molmed.2004.04.006
                7128344
                15177193
                05b93735-3cc4-4bf1-b649-0ae921e780bf
                Copyright © 2004 Elsevier Ltd. All rights reserved.

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                Molecular medicine
                Molecular medicine

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