The C-terminal activation domain of the STAT-1 transcription factor is necessary and sufficient for stress-induced apoptosis.
It has previously been demonstrated that the STAT-1 transcription factor plays a key role in apoptosis induced by the cellular regulatory factors interferon gamma and TNF-alpha. Here we demonstrate that cells lacking STAT-1 show reduced cell death/apoptosis in response to stressful stimuli such as heat or ischaemia. Expression of STAT-1 in these cells does not enhance basal cell death but restores sensitivity to stress-induced death whereas this effect is not observed upon over-expression of STAT-3. Enhanced sensitivity to stress-induced cell death requires the C-terminal activation domain of STAT-1 and the phosphorylation sites at tyrosine 701 and serine 727. Moreover, we show for the first time in any system that the isolated C-terminal domain of STAT-1 is able to enhance stress-induced cell death in the absence of the DNA binding domain or any other region of STAT-1. Hence, STAT-1 plays a key role in stress-induced cell death, potentially acting via a novel co-activator-type mechanism and represents a possible therapeutic target for strategies aimed at minimising cell death, for example, following ischaemic injury.
Janjua
S
S
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Stephanou
A
A
Latchman
D S
DS
D017209:Apoptosis / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D018869:Heat-Shock Response / Q000235:genetics; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; D012694:Serine