Differential activation of some transcription factors during rat liver ischemia, reperfusion, and heat shock.
Cells respond to external stimuli by changes in gene expression that are largely dependent on transcription factors (TFs). We studied the behavior of some TFs in rat liver during ischemia, postischemic reperfusion, and heat shock. Knowledge of the conditions at the end of ischemia is essential to understand changes occurring at reperfusion. The TFs investigated are known to be typically responsive to heat shock (HSF), hypoxia (HIF-1), pro- and antioxidant conditions (AP-1), or to various environmental changes (HNF-1 and ATF/CREB family). The most relevant new information includes the following: 1) Liver ischemia activates extremely rapidly the DNA binding capacity of HSF, soon followed by analogous activation of HIF-1 and AP-1. 2) After a certain lag time from the activation of HIF-1, mRNAs accumulate for two glycolytic enzymes, in particular Aldolase A and Heme Oxygenase 1, which contain HIF-1 sequences in their promoters. 3) Reperfusion, which is known to further increase the binding of HSF and to induce NFkappaB binding, abrogates or decreases the binding of HIF-1 and AP-1, stimulated by ischemia, and activates the binding of ATF/CREB. Later on, a second peak of AP-1 binding is induced. 4) Heat shock activates both ischemia-responsive and reperfusion-responsive TFs. 5) Preliminary experiments of supergelshift reveal that the activation of AP-1 at reperfusion or upon heat shock may result from the different involvement of the component subunits.
Istituto di Patologia Generale dell'Università degli Studi di Milano, Centro di Studio sulla Patologia Cellulare del CNR, Milan, Italy.
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Bernelli-Zazzera
D000818:Animals; D015152:Blotting, Northern; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D010450:Endopeptidases; D015870:Gene Expression / Q000502:physiology; D018869:Heat-Shock Response / Q000235:genetics*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015345:Oligonucleotide Probes; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D010450:Endopeptidases; C473330:USP6 protein, human; D043222:Ubiquitin Thiolesterase