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.
Heat 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.
Piper
Peter W
PW
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK. piper@bsm.bio.ucl.ac.uk
Panaretou
Barry
B
Millson
Stefan H
SH
Truman
Andrew
A
Mollapour
Mehdi
M
Pearl
Laurence H
LH
Prodromou
Chrisostomos
C
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010957:Plasmids / Q000235:genetics; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
D000900:Anti-Bacterial Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D011809:Quinones; D017828:Rifabutin; C112765:tanespimycin; C035359:monorden; C001277:geldanamycin