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J Biol Chem, Vol. 273, Issue 26, 16446-16452, June 26, 1998

Activation of the Heat Shock Factor 1 by Serine Protease Inhibitors
AN EFFECT ASSOCIATED WITH NUCLEAR FACTOR-B INHIBITION

Antonio Rossi, Giuliano Elia, and M. Gabriella Santoro^§

From the  Institute of Experimental Medicine, Consiglio Nazionale delle Ricerche, Via del Fosso del Cavaliere and the ^§ Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy

Heat shock proteins (HSPs) have a cytoprotective role in several human diseases, including ischemia and viral infection. Nuclear factor-B (NF-B) is a critical regulator of inflammation and virus replication. Here we report that a class of serine protease inhibitors with NF-B-inhibitory activity are potent HSP inducers via activation of heat shock transcription factor 1 (HSF1) in human cells. 3,4-Dichloroisocoumarin, the most effective compound, rapidly induces HSF1 DNA binding activity and phosphorylation, leading to transcription and translation of heat shock genes for a period of several hours. HSF1 activation is independent of de novo protein synthesis and is correlated in a concentration- and time-dependent manner with NF-B inhibition. Cysteine protease inhibitors E64 and calpain inhibitor II, which do not block NF-B activation, do not induce HSF DNA binding activity. HSP induction by 3,4-dichloroisocoumarin is associated with antiviral activity during rhabdovirus infection. These results identify a new class of HSP inducers and indicate a link between the regulatory pathways of HSF and NF-B, suggesting novel strategies to simultaneously switch on cytoprotective genes and down-regulate inflammatory and viral genes.

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