title: Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia.
abstract: Focal ischemia induced by middle cerebral artery occlusion (MCAO) to adult rats results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Upstream from the cell death promoters and executioners are several kinases that, once activated by phosphorylation, may activate several transcription factor substrates involved in cell death and cell survival. In the present study we examined, by immunohistochemistry, the expression of phosphorylated (active) mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK), stress-activated protein kinase (SAPK), c-Jun N-terminal kinase (JNK) and p-38 kinase at early stages (1-4 h) following 1 h of MCAO in the rat. The expression of phosphorylation-dependent, active transcription substrates of these kinases, including cyclic AMP-responsive element-binding protein (CREB) Alk-1, ATF-2, c-Myc and c-Jun was examined at early stages following reperfusion. Increased nuclear phosphorylated SAPK/JNK (SAPK/JNK-P) and c-Jun-PSer63, and reduced CREB-P, occurred in the infarct core at 1 h following reperfusion, suggesting increased phosphorylated SAPK/JNK and c-JunSer63, together with decreased phospho-CREB associated with cell death in the infarct core. However, increased cytoplasmic expression of MAPK/ERK-P, SAPK/JNK-P, p38-P, CREB-P, Elk-1-P, c-Myc-P, ATF-2-P and c-Jun-P occurred in the region bordering the infarct core (penumbra) at 4 h following reperfusion. This indicates that different signals converge in the cytoplasm of neurons located at the borders of the infarct at 4 h following reperfusion, revealing the struggle of death promoters and life facilitators at the penumbra. Whether phosphorylated kinases and specific substrates participate in promoting cell death or survival in the penumbra probably depends on additional factors and on the interaction with other proteins.
authors.affiliation: Institut de Neuropatologia, Servei d'Anatomia Patològica, Hospital Princeps d'Espanya, Universitat de Barcelona, Campus de Bellvitge, carrer Feixa LLarga sn, 08907 Hospitalet de Llobregat, Spain. 8082ifa@comb.es
authors.forename: I
authors.initials: I
authors.lastname: Ferrer
authors.forename: B
authors.initials: B
authors.lastname: Friguls
authors.forename: E
authors.initials: E
authors.lastname: Dalfó
authors.forename: A M
authors.initials: AM
authors.lastname: Planas
mesh_terms: D051696:Activating Transcription Factors; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002545:Brain Ischemia / Q000201:enzymology* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051696:Activating Transcription Factors; D001798:Blood Proteins; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases