期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 24, 期 2, 页码 661-666出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.11.059
关键词
Heat shock protein 90 (hsp90); Tetratricopeptide-repeat (TPR); FKBP51; FKBP52; Heat shock response; Heat shock factor 1 (HSF1)
资金
- University of New South Wales
- Frasch foundation [658-HF07]
- NIH [1R01CA137873]
- NIH MIRT
When a cell encounters external stressors, such as lack of nutrients, elevated temperatures, changes in pH or other stressful environments, a key set of evolutionarily conserved proteins, the heat shock proteins (hsps), become overexpressed. Hsps are classified into six major families with the hsp90 family being the best understood; an increase in cell stress leads to increased levels of hsp90, which leads to cellular protection. A hallmark of hsp90 inhibitors is that they induce a cell rescue mechanism, the heat shock response. We define the unique molecular profile of a compound (SM145) that regulates hormone receptor protein levels through hsp90 inhibition without inducing the heat shock response. Modulation of the binding event between heat shock protein 90 and the immunophilins/homologs using SM145, leads to a decrease in hormone receptor protein levels. Unlike N-terminal hsp90 inhibitors, this hsp90 inhibitor does not induce a heat shock response. This work is proof of principle that controlling hormone receptor expression can occur by inhibiting hsp90 without inducing pro-survival protein heat shock protein 70 (hsp70) or other proteins associated with the heat shock response. Innovatively, we show that blocking the heat shock response, in addition to hsp90, is key to regulating hsp90-associated pathways. (C) 2013 Elsevier Ltd. All rights reserved.
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