Glycogen synthase kinase 3β inhibitors protect hippocampal neurons from radiation-induced apoptosis by regulating MDM2-p53 pathway.

Thotala DK, Hallahan DE, Yazlovitskaya EM
Cell Death Differ. 2012 19 (3): 387-96

PMID: 21738215 · PMCID: PMC3193912 · DOI:10.1038/cdd.2011.94

Exposure of the brain to ionizing radiation can cause neurocognitive deficiencies. The pathophysiology of these neurological changes is complex and includes radiation-induced apoptosis in the subgranular zone of the hippocampus. We have recently found that inhibition of glycogen synthase kinase 3β (GSK-3β) resulted in significant protection from radiation-induced apoptosis in hippocampal neurons. The molecular mechanisms of this cytoprotection include abrogation of radiation-induced accumulation of p53. Here we show that pretreatment of irradiated HT-22 hippocampal-derived neurons with small molecule inhibitors of GSK-3β SB216763 or SB415286, or with GSK-3β-specific shRNA resulted in accumulation of the p53-specific E3 ubiquitin ligase MDM2. Knockdown of MDM2 using specific shRNA or chemical inhibition of MDM2-p53 interaction prevented the protective changes triggered by GSK-3β inhibition in irradiated HT-22 neurons and restored radiation cytotoxicity. We found that this could be due to regulation of apoptosis by subcellular localization and interaction of GSK-3β, p53 and MDM2. These data suggest that the mechanisms of radioprotection by GSK-3β inhibitors in hippocampal neurons involve regulation of MDM2-dependent p53 accumulation and interactions between GSK-3β, MDM2 and p53.

MeSH Terms (14)

Animals Apoptosis Cell Line, Transformed Enzyme Inhibitors Gamma Rays Glycogen Synthase Kinase 3 Glycogen Synthase Kinase 3 beta Hippocampus Mice Neurons Protein Transport Proto-Oncogene Proteins c-mdm2 Radiation Tolerance Tumor Suppressor Protein p53

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