Activation of the heat shock factor 1 by serine protease inhibitors. An effect associated with nuclear factor-kappaB inhibition.
Heat shock proteins (HSPs) have a cytoprotective role in several human diseases, including ischemia and viral infection. Nuclear factor-kappaB (NF-kappaB) is a critical regulator of inflammation and virus replication. Here we report that a class of serine protease inhibitors with NF-kappaB-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-kappaB inhibition. Cysteine protease inhibitors E64 and calpain inhibitor II, which do not block NF-kappaB 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-kappaB, suggesting novel strategies to simultaneously switch on cytoprotective genes and down-regulate inflammatory and viral genes.
Rossi
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A
Institute of Experimental Medicine, Consiglio Nazionale delle Ricerche, Via del Fosso del Cavaliere, 00133 Rome, Italy.
Elia
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G
Santoro
M G
MG
D003374:Coumarins / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D049934:Isocoumarins; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*
D003374:Coumarins; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D049934:Isocoumarins; D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; D014157:Transcription Factors; C046235:3,4-dichloroisocoumarin; D004247:DNA