EXPRESSION OF C-FOS AND C-JUN FAMILY GENES AFTER FOCAL CEREBRAL-ISCHEMIA

The expression of the protooncogenes, c-fos, jun B, c-jun, and jun D w as investigated in a rat focal cerebral ischemia model by Northern ana lysis and in situ hybridization. Severe ischemia (reduction of regiona l blood flow by 88-92%) in this model is confined to cerebral cortex i rrigated by the right middle cerebral artery. Ischemia for 30 minutes, which caused only slight cortical damage (infarct size, < 10 mm3), in duced both jun B and c-fos mRNAs exclusively in the right cerebral cor tex. Ischemia for 90 minutes, which led to large cortical infarction ( infarct size, > 140 mm3), also induced the expression of these two gen es in the right cerebral cortex as well as the ipsilateral hippocampus . The latter sustained very mild ischemia (reduction of regional blood flow by 10-20%). The coinduction of jun B and c-fos expression occurr ed immediately after reperfusion and peaked at 60 minutes after reperf usion. The expression of c-jun was enhanced in a similar pattern, but at a much lower magnitude. In contrast, no change in jun D expression was observed. Nuclear run-on assays indicated that the increase in c-f os, jun B, and c-jun mRNA levels was due to the increase of transcript ion rate in these genes. Mobility shift assays showed a basal DNA bind ing activity of transcription factor AP-1 in the right cerebral cortex . Ischemia for 30 or 90 minutes followed by reperfusion for 4 hours re sulted in a four- to sixfold increase of AP-1 binding activity. The en hanced DNA binding activity persisted for as long as 24 hours. These r esults suggest that the enhanced expression of AP-1, a general transcr iption factor, may play a role in the alteration of gene regulation in the ischemic cortex.