z-logo
open-access-imgOpen Access
Sensitivity to Hsp90‐targeting drugs can arise with mutation to the Hsp90 chaperone, cochaperones and plasma membrane ATP binding cassette transporters of yeast
Author(s) -
Piper Peter W.,
Millson Stefan H.,
Mollapour Mehdi,
Panaretou Barry,
Siligardi Giuliano,
Pearl Laurence H.,
Prodromou Chrisostomos
Publication year - 2003
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1033.2003.03866.x
Subject(s) - hsp90 , geldanamycin , chaperone (clinical) , heat shock protein , atp binding cassette transporter , biochemistry , biology , hsp90 inhibitor , saccharomyces cerevisiae , microbiology and biotechnology , chemistry , yeast , transporter , medicine , gene , pathology
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 .

The content you want is available to Zendy users.

Already have an account? Click here to sign in.
Having issues? You can contact us here