Sensitivity to Hsp90-targeting drugs can arise with mutation to the Hsp90 chaperone, cochaperones and plasma membrane ATP binding cassette transporters of yeast.
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.
Piper
Peter W
PW
Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield, UK. peter.piper@sheffield.ac.uk
Millson
Stefan H
SH
Mollapour
Mehdi
M
Panaretou
Barry
B
Siligardi
Giuliano
G
Pearl
Laurence H
LH
Prodromou
Chrisostomos
C
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D002462:Cell Membrane / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D018869:Heat-Shock Response / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins