ITZ-1, a client-selective Hsp90 inhibitor, efficiently induces heat shock factor 1 activation.

ITZ-1 is a chondroprotective agent that inhibits interleukin-1beta-induced matrix metalloproteinase-13 (MMP-13) production and suppresses nitric oxide-induced chondrocyte death. Here we describe its mechanisms of action. Heat shock protein 90 (Hsp90) was identified as a specific ITZ-1-binding protein. Almost all known Hsp90 inhibitors have been reported to bind to the Hsp90 N-terminal ATP-binding site and to simultaneously induce degradation and activation of its multiple client proteins. However, within the Hsp90 client proteins, ITZ-1 strongly induces heat shock factor-1 (HSF1) activation and causes mild Raf-1 degradation, but scarcely induces degradation of a broad range of Hsp90 client proteins by binding to the Hsp90 C terminus. These results may explain ITZ-1's inhibition of MMP-13 production, its cytoprotective effect, and its lower cytotoxicity. These results suggest that ITZ-1 is a client-selective Hsp90 inhibitor. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Citation

Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Tomoko Chikatsu, Shinji Morimoto, Yasunori Funabashi, Hiroaki Omae, Takashi Ito, Yukio Yoneda, Masayuki Takizawa. ITZ-1, a client-selective Hsp90 inhibitor, efficiently induces heat shock factor 1 activation. Chemistry & biology. 2010 Jan 29;17(1):18-27

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PMID: 20142037

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