Yeast is selectively hypersensitised to heat shock protein 90 (Hsp90)-targetting drugs with heterologous expression of the human Hsp90β, a property that can be exploited in screens for new Hsp90 chaperone inhibitors

Piper, P. W. and Panaretou, B. and Millson, S. H. and Trumana, A. and Mollapour, M. and Pearl, L. H. and Prodromou, C. (2003) Yeast is selectively hypersensitised to heat shock protein 90 (Hsp90)-targetting drugs with heterologous expression of the human Hsp90β, a property that can be exploited in screens for new Hsp90 chaperone inhibitors. Gene, 302 (1-2). pp. 165-170. ISSN 0378-1119

Full content URL: http://dx.doi.org/10.1016/S0378-1119(02)01102-2

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Item Type:Article
Item Status:Live Archive

Abstract

Heat shock protein 90 (Hsp90) is essential for activation of many of the most important regulatory proteins of eukaryotic cells. It is an extremely conserved protein, such that heterologous expressions of either human Hsp90β or Caenorhabditis elegans Hsp90 will provide the essential Hsp90 function in yeast. The ability of these metazoan Hsp90s to provide this Hsp90 function to yeast cells requires Sti, a Hsp90 system cochaperone. Yeast that is expressing human Hsp90β in place of the normal native yeast Hsp90 is selectively hypersensitised to Hsp90 inhibitor drugs. Hsp90 drugs are promising anticancer agents, their administration simultaneously destabilizing a number of the proteins critical to multistep carcinogenesis. Though one of these drugs (17-allylaminogeldanamycin, 17-AAG) is now progressing to Phase 2 clinical trials, there is a pressing need to identify selective Hsp90 inhibitors that are more soluble than 17-AAG. High-throughput screening for chemical agents that exert greater inhibitory effects against yeast expressing the human Hsp90β relative to yeast expressing its native Hsp90 should therefore facilitate the search for new Hsp90 inhibitors. © 2002 Elsevier Science B.V. All rights reserved.

Keywords:Anticancer agents, Chaperone inhibitors, Drug resistance, Geldanamycin, Radicicol, Saccaromyces cerevisiae
Subjects:B Subjects allied to Medicine > B990 Subjects Allied to Medicine not elsewhere classified
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
C Biological Sciences > C500 Microbiology
Divisions:College of Science > School of Life Sciences
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ID Code:15358
Deposited On:21 Oct 2014 15:03

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