title: Eukaryotic initiation factor 4E degradation during brain ischemia.
abstract: Suppression of protein synthesis in the brain following an ischemic insult has been thought to occur because of inhibition of translation initiation. All eukaryotic mRNAs, with the exception of heat-shock transcripts, require the activity of eukaryotic initiation factor (eIF) 4E for formation of the translation initiation complex, and eIF-4E availability is rate-limiting. The response of brain eIF-4E concentration and phosphorylation following decapitation ischemia was studied in rat brain homogenates after electrophoresis and western blotting with antibodies against eIF-4E and phosphoserine, respectively. There was no change in level of eIF-4E after 5 min of ischemia (p = 0.82 vs. time 0), but it had decreased 32 (p = 0.01) and 57% (p = 0.006) after 10 and 20 min of ischemia, respectively. There was no loss of serine phosphorylation on eIF-4E beyond signal loss observed due to degradation of the protein itself (p = 0.31). In vitro exposure of eIF-4E to activated mu-calpain resulted in a 50% loss in 10 min of eIF-4E on western blots. If active eIF-4E is required for translation of its own mRNA, degradation of this protein during ischemia, possibly by activated mu-calpain, could be a direct mechanism of irreversible neuronal injury, and the rate of proteolysis of eIF-4E could place an upper time limit on the maximal duration of global brain ischemia compatible with neurologic recovery.
authors.affiliation: Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Neumar
authors.forename: D J
authors.initials: DJ
authors.lastname: DeGracia
authors.forename: B C
authors.initials: BC
authors.lastname: White
authors.forename: P J
authors.initials: PJ
authors.lastname: McDermott
authors.forename: D R
authors.initials: DR
authors.lastname: Evans
authors.forename: G S
authors.initials: GS
authors.lastname: Krause
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002154:Calpain / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D010768:Phosphoserine; D002154:Calpain