PKCϵ phosphorylation regulates the mitochondrial translocation of ATF2 in ischemia-induced neurodegeneration

Abstract

Background: Global cerebral ischemia triggers neurodegeneration in the hippocampal CA1 region, but the mechanism of neuronal death remains elusive. The epsilon isoform of protein kinase C (PKCϵ) has recently been identified as a master switch that controls the nucleocytoplasmic trafficking of ATF2 and the survival of melanoma cells. It is of interest to assess the role of PKCϵ-ATF2 signaling in neurodegeneration. Results: Phosphorylation of ATF2 at Thr-52 was reduced in the hippocampus of PKCϵ null mice, suggesting that ATF2 is a phosphorylation substrate of PKCϵ. PKCϵ protein concentrations were significantly reduced 4, 24, 48 and 72 h after transient global cerebral ischemia, resulting in translocation of nuclear ATF2 to the mitochondria. Degenerating neurons staining positively with Fluoro-Jade C exhibited cytoplasmic ATF2. Conclusions: Our results support the hypothesis that PKCϵ regulates phosphorylation and nuclear sequestration of ATF2 in hippocampal neurons during ischemia-induced neurodegeneration.