Heat stress downregulates FLIP and sensitizes cells to Fas receptor-mediated apoptosis

S E F Tran, A Meinander, T H Holmström, A Rivero-Müller, K M Heiskanen, E K Linnau, M J Courtney, D D Mosser, L Sistonen, J E Eriksson

Research output: Contribution to journalArticleScientificpeer-review

57 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1137–1147
Number of pages11
JournalCell Death and Differentiation
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 2003
MoE publication typeA1 Journal article-refereed

Keywords

  • Amino Acid Chloromethyl Ketones/pharmacology
  • Annexin A5/metabolism
  • Apoptosis/drug effects
  • Blotting, Western
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins/analysis
  • Caspase 8
  • Caspase Inhibitors
  • Caspases/metabolism
  • DNA-Binding Proteins/metabolism
  • Death Domain Receptor Signaling Adaptor Proteins
  • Down-Regulation
  • Electrophoretic Mobility Shift Assay
  • Fas Ligand Protein
  • Flow Cytometry
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • HSP70 Heat-Shock Proteins/metabolism
  • HeLa Cells
  • Heat Shock Transcription Factors
  • Heat-Shock Response/physiology
  • Hot Temperature
  • Humans
  • Immunoglobulin M/pharmacology
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells
  • Luminescent Proteins/genetics
  • MAP Kinase Kinase 4
  • MAP Kinase Signaling System/physiology
  • Membrane Glycoproteins/agonists
  • Membrane Potentials/physiology
  • Microscopy, Polarization
  • Mitochondria/physiology
  • Mitogen-Activated Protein Kinase Kinases/metabolism
  • Mitogen-Activated Protein Kinases/metabolism
  • Oligopeptides/pharmacology
  • Proto-Oncogene Proteins c-jun/metabolism
  • Receptors, Tumor Necrosis Factor/antagonists & inhibitors
  • Transcription Factors
  • fas Receptor/immunology

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