Yeast is selectively hypersensitised to heat shock protein 90 (Hsp90)-targetting drugs with heterologous expression of the human Hsp90beta, a property that can be exploited in screens for new Hsp90 chaperone inhibitors

Piper, Peter W, Panaretou, Barry, Millson, Stefan H, Truman, Andrew, Mollapour, Mehdi, Pearl, Laurence and Prodromou, Chrisostomos (2003) Yeast is selectively hypersensitised to heat shock protein 90 (Hsp90)-targetting drugs with heterologous expression of the human Hsp90beta, a property that can be exploited in screens for new Hsp90 chaperone inhibitors. Gene, 302 (1-2). pp. 165-170. ISSN 0378-1119

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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 Hsp90beta 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 Hsp90beta 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 Hsp90beta relative to yeast expressing its native Hsp90 should therefore facilitate the search for new Hsp90 inhibitors.

Item Type: Article
Keywords: Anti-Bacterial Agents/*pharmacology Benzoquinones Cell Division/drug effects/genetics Drug Screening Assays, Antitumor/methods HSP90 Heat-Shock Proteins/*antagonists & inhibitors/genetics Humans Lactams, Macrocyclic Lactones/pharmacology Macrolides Microbial Sensitivity Tests Mutation Plasmids/genetics Quinones/pharmacology Rifabutin/*analogs & derivatives/pharmacology Saccharomyces cerevisiae/*drug effects/genetics/growth & development
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
R Medicine
Depositing User: Chrisostomos Prodromou
Date Deposited: 25 Feb 2015 08:55
Last Modified: 25 Feb 2015 08:55
URI: http://sro.sussex.ac.uk/id/eprint/44356
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