Sensitivity to Hsp90-targeting drugs can arise with mutation to the Hsp90 chaperone, cochaperones and plasma membrane ATP binding cassette transporters of yeast

Piper, Peter W, Millson, Stefan H, Mollapour, Mehdi, Panaretou, Barry, Siligardi, Giuliano, Pearl, Laurence H and Prodromou, Chrisostomos (2003) Sensitivity to Hsp90-targeting drugs can arise with mutation to the Hsp90 chaperone, cochaperones and plasma membrane ATP binding cassette transporters of yeast. European Journal of Biochemistry, 270 (23). pp. 4689-4695. ISSN 0014-2956

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Abstract

The Hsp90 molecular chaperone catalyses the final activation step of many of the most important regulatory proteins of eukaryotic cells. The antibiotics geldanamycin and radicicol act as highly selective inhibitors of in vivo Hsp90 function through their ability to bind within the ADP/ATP binding pocket of the chaperone. Drugs based on these compounds are now being developed as anticancer agents, their administration having the potential to inactivate simultaneously several of the targets critical for counteracting multistep carcinogenesis. This investigation used yeast to show that cells can be rendered hypersensitive to Hsp90 inhibitors by mutation to Hsp90 itself (within the Hsp82 isoform of yeast Hsp90, the point mutations T101I and A587T); with certain cochaperone defects and through the loss of specific plasma membrane ATP binding cassette transporters (Pdr5p, and to a lesser extent, Snq2p). The T101I hsp82 and A587T hsp82 mutations do not cause higher drug affinity for purified Hsp90 but may render the in vivo chaperone cycle more sensitive to drug inhibition. It is shown that these mutations render at least one Hsp90-dependent process (deactivation of heat-induced heat shock factor activity) more sensitive to drug inhibition in vivo.

Item Type: Article
Keywords: ATP-Binding Cassette Transporters/*antagonists & inhibitors/genetics Cell Membrane/*chemistry HSP90 Heat-Shock Proteins/*antagonists & inhibitors/*genetics Heat-Shock Response/drug effects Inhibitory Concentration 50 Microbial Sensitivity Tests Molecular Chaperones/*antagonists & inhibitors/genetics Point Mutation/*genetics Saccharomyces cerevisiae/*drug effects/metabolism Saccharomyces cerevisiae Proteins/antagonists & inhibitors/genetics
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 08:43
Last Modified: 25 Feb 2015 08:43
URI: http://sro.sussex.ac.uk/id/eprint/44355
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