Abstract
The heat shock response and death receptor-mediated apoptosis are both key physiological determinants of cell survival. We found that exposure to a mild heat stress rapidly sensitized Jurkat and HeLa cells to Fas-mediated apoptosis. We further demonstrate that Hsp70 and the mitogen-activated protein kinases, critical molecules involved in both stress-associated and apoptotic responses, are not responsible for the sensitization. Instead, heat stress on its own induced downregulation of FLIP and promoted caspase-8 cleavage without triggering cell death, which might be the cause of the observed sensitization. Since caspase-9 and -3 were not cleaved after heat shock, caspase-8 seemed to be the initial caspase activated in the process. These findings could help understanding the regulation of death receptor signaling during stress, fever, or inflammation.
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Abbreviations
- DISC:
-
death-inducing signaling complex
- DR:
-
death receptor
- ERK1/2:
-
extracellular-regulated kinase 1 and 2
- HS:
-
heat shock
- HSE:
-
heat shock element
- HSF:
-
heat shock factor
- Hsp:
-
heat shock protein
- JNK:
-
c-Jun N-terminal kinase
- MAPK:
-
mitogen-activated protein kinase
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Acknowledgements
We thank Peter Krammer (German Cancer Research Center, Heidelberg, Germany) for caspase-8 and FLIP antibodies, Jürg Tschopp (Institute of Biochemistry, University of Lausanne, Switzerland) for Fas ligand, and John Kyriakis (Diabetes Research Laboratory, Massachusetts General Hospital, Charlestown, MA, USA) for the SEK1 plasmid. We also thank the other members of our laboratories for technical help and critical comments on the manuscript. Financial support from the Academy of Finland, Finnish Cancer Organizations, Sigrid Jusélius Foundation, Erna and Victor Hasselblad Foundation, Nordic Academy for Advanced Study (NorFA), Magnus Ehrnrooth Foundation, Åbo Akademi University, and University of Turku is gratefully acknowledged. SEFT was supported by the Turku Graduate School of Biomedical Sciences.
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Tran, S., Meinander, A., Holmström, T. et al. Heat stress downregulates FLIP and sensitizes cells to Fas receptor-mediated apoptosis. Cell Death Differ 10, 1137–1147 (2003). https://doi.org/10.1038/sj.cdd.4401278
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DOI: https://doi.org/10.1038/sj.cdd.4401278
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