Persistent phosphorylation of cyclic amp responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain
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Abstract
The transcription factors cyclic AMP responsive element-binding protein (CREB) and
activating transcription factor-2 were studied in rat brains subjected to 15 min ischemia
followed by varied periods of reperfusion using western blot and immunocytochemical
analyses. The total amounts of both CREB and activating transcription factor-2 were
not altered in the hippocampus after ischemia. In contrast, levels of the phosphorylated
forms of both transcription factors decreased during ischemia but rebounded following
reperfusion. The phospho-forms of CREB and activating transcription factor-2 showed
regional and temporal differences in their expression. Phospho-CREB was increased
relative to control levels at 30 min, and continued to increase for at least three
days postischemia, mainly in dentate granule cells. The level of phospho-activating
transcription factor-2 appeared to be higher in CAI pyramidal cells than in dentate
granule cells after ischemia. The present findings suggest that the signaling pathways
for phosphorylation of CREB may be neuroprotective for dentate cells, which are relatively
resistant to ischemic insults. The increased phospho-activating transcription factor-2
may reflect increased stresses in these neurons. The more modest activation of CREB
pathways in CA1 neurons may not be enough to overcome the increased stresses in these
neurons, contributing to delayed neuronal death.