Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1.
The novel hydroxylamine derivative, bimoclomol, has been shown previously to act as a co-inducer of several heat shock proteins (Hsp-s), enhancing the amount of these proteins produced following a heat shock compared to heat shock alone. Here we show that the co-inducing effect of bimoclomol on Hsp expression is mediated via the prolonged activation of the heat shock transcription factor (HSF-1). Bimoclomol effects are abolished in cells from mice lacking HSF-1. Moreover, bimoclomol binds to HSF-1 and induces a prolonged binding of HSF-1 to the respective DNA elements. Since HSF-1 does not bind to DNA in the absence of stress, the bimoclomol-induced extension of HSF-1/DNA interaction may contribute to the chaperone co-induction of bimoclomol observed previously. These findings indicate that bimoclomol may be of value in targeting HSF-1 so as to induce up-regulation of protective Hsp-s in a non-stressful manner and for therapeutic benefit.
Hargitai
Judit
J
Biorex R&D Co, H-8201 Veszprém, PO Box 348, Hungary.
Lewis
Hannah
H
Boros
Imre
I
Rácz
Tímea
T
Fiser
András
A
Kurucz
István
I
Benjamin
Ivor
I
Vígh
László
L
Pénzes
Zoltán
Z
Csermely
Péter
P
Latchman
David S
DS
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D007094:Imides / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D020871:RNA Stability; D020218:Response Elements; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D007094:Imides; D046911:Macromolecular Substances; D011725:Pyridines; D014157:Transcription Factors; C108730:bimoclomol