[Reciprocal modification of Fas activation and stress protein response decides apoptosis or resistance development of cells].
Activation of heat shock factor (HSF)-1 DNA binding and heat shock protein (hsp)-70 expression enable resistance of cells to various forms of stress and maintain cell survival. Fas, a membrane-bound protein, is a central pro-apoptotic factor. Its activation leads to a cascade of events resulting in programmed cell death. Herein, these two mechanisms with contrary functions, promoting either cell survival or death, were addressed for their potential to inhibit each other's activation. Induction of Fas-mediated signalling was followed by a rapid decrease of HSF1 DNA binding and inducible hsp70 expression. Inhibition of HSF1 DNA binding was demonstrated to be based on absent hyperphosphorylation of HSF1 during FAS-signalling. These effects of Fas-activation on the HSF1/hsp70 stress response were blocked by ICE (caspase 1)-inhibitors, suggesting an ICE-mediated process. Furthermore, inhibition of HSF1/hsp70 was accompanied by an increase of apoptosis rates from 20% to 50% in response to heat stress. When analyzing Fas-mediated apoptosis in the presence of HSF1/hsp70 activation, decreased apoptosis rates were detected with induced expression of hsp70 but not with activation of HSF1-DNA binding alone. Thus, we conclude that inhibition of the HSF1/hsp70 stress response during Fas-mediated apoptosis and vice versa may facilitate a cell to pass a previously chosen pathway, stress resistance or apoptosis.
Schett
G
G
Abteilung Rheumatologie der Universitätsklinik für Innere Medizin III, Wien. georg.schett@akh-wien.ac.at
Steiner
C W
CW
Winkler
S
S
Graninger
W
W
Smolen
J
J
Xu
Q
Q
Steiner
G
G
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured / Q000502:physiology*; D020298:U937 Cells; D019014:fas Receptor / Q000235:genetics*
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D019014:fas Receptor