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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
journal contribution
posted on 2023-06-08, 14:43 authored by Peter W Piper, Barry Panaretou, Stefan H Millson, Andrew Truman, Mehdi Mollapour, Laurence PearlLaurence Pearl, Chrisostomos ProdromouChrisostomos ProdromouHeat 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.
History
Publication status
- Published
Journal
GeneISSN
0378-1119Publisher
ElsevierExternal DOI
Issue
1-2Volume
302Page range
165-170Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-02-25Usage metrics
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No categories selectedKeywords
Anti-Bacterial Agents/*pharmacologyBenzoquinonesCell Division/drug effects/geneticsDrug Screening AssaysAntitumor/methodsHSP90 Heat-Shock Proteins/*antagonists & inhibitors/geneticsHumansLactamsMacrocyclicLactones/pharmacologyMacrolidesMicrobial Sensitivity TestsMutationPlasmids/geneticsQuinones/pharmacologyRifabutin/*analogs & derivatives/pharmacologySaccharomyces cerevisiae/*drug effects/genetics/growth & development
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