TAILIEUCHUNG - Báo cáo khoa học: 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 activa-tion step of many of themost important regulatory proteins of eukaryotic cells. The antibiotics geldanamycin and rad-icicol act as highly selective inhibitors of in vivo Hsp90 function through their ability to bindwithin 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 sim-ultaneously several of the targets critical for counteracting multistep carcinogenesis. . | Eur. J. Biochem. 270 4689-4695 2003 FEBS 2003 doi Sensitivity to Hsp90-targeting drugs can arise with mutation to the Hsp90 chaperone cochaperones and plasma membrane ATP binding cassette transporters of yeast Peter W. Piner1. Stefan H. Millson1 Mehdi Mollanour1 Barrv Panaretou2. Giuliano Siliaardi3 . BB. Laurence H. Pearl4 and Chrisostomos Prodromou4 1 Department of Molecular Biology and Biotechnology University of Sheffield Firth Court Western Bank Sheffield UK 2 Division of Life Sciences and 3Pharmaceutical Optical Spectroscopy Centre Department of Pharmacy King s College London Franklin-Wilkins Building London UK 4 Section for Structural Biology Institute of Cancer Research Chester Beatty Laboratories London UK The Hsp90 molecular chaperone catalyses the final activation step of many of the most important regulatory proteins of eukaryotic cells. The antibiotics geldanamycin and rad-icicol 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 usedyeast 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 ATT binding cassette transporters Tdr5p and to a lesser extent Snq2p . The T101I hsp82 and 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 .

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