Hypoxia/re-oxygenation-induced, redox-dependent activation of STAT1 (signal transducer and activator of transcription 1) confers resistance to apoptotic cell death via hsp70 induction.
STAT1 (signal transducer and activator of transcription 1) is potentially involved in cell survival, as well as cell death, in different types of cells. The present study was designed to examine the effects of STAT1 on hypoxia/re-oxygenation (H/R)-induced cell death and/or survival, and the underlying mechanisms of any such effects. H/R was shown to induce apoptotic cell death of rat hepatocytes. The addition of a STAT1-specific inhibitor, fludarabine, significantly increased the fraction of apoptotic cells after H/R. Following H/R, STAT1 was activated and sequential phosphorylation of Tyr701 and Ser727 was observed, which could be inhibited by the antioxidant N-acetyl-L-cysteine. Tyrosine and serine phosphorylation of STAT1 was mediated by Janus kinase 2 and phosphoinositide 3-kinase/Akt kinase respectively in a redox-dependent manner following H/R. STAT1-induced HSP70 (heat-shock protein 70) expression and the suppression of apoptosis occurred concomitantly. In conclusion, STAT1 activation, in a redox-dependent manner, following H/R may play crucial roles in cell survival, at least partly via HSP70 induction.
Terui
Keita
K
Bioengineering Laboratory, Department of Innovative Surgery National Research Institute for Child Health and Development 3-35-31, Taishi-do, Setagaya, Tokyo, 154-8567, Japan.
Haga
Sanae
S
Enosawa
Shin
S
Ohnuma
Naomi
N
Ozaki
Michitaka
M
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053614:Janus Kinase 2; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011917:Rats, Inbred Lew; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000111:Acetylcysteine; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D053614:Janus Kinase 2; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D020032:Tyrphostins; D014740:Vidarabine; C494081:Stat1 protein, rat; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507927:Jak2 protein, rat; C494920:Akt1 protein, rat; C024352:fludarabine