| First Author | Thotala DK | Year | 2012 |
| Journal | Cell Death Differ | Volume | 19 |
| Issue | 3 | Pages | 387-96 |
| PubMed ID | 21738215 | Mgi Jnum | J:203618 |
| Mgi Id | MGI:5527531 | Doi | 10.1038/cdd.2011.94 |
| Citation | Thotala DK, et al. (2012) Glycogen synthase kinase 3beta inhibitors protect hippocampal neurons from radiation-induced apoptosis by regulating MDM2-p53 pathway. Cell Death Differ 19(3):387-96 |
| abstractText | 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 3beta (GSK-3beta) 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-3beta SB216763 or SB415286, or with GSK-3beta-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-3beta 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-3beta, p53 and MDM2. These data suggest that the mechanisms of radioprotection by GSK-3beta inhibitors in hippocampal neurons involve regulation of MDM2-dependent p53 accumulation and interactions between GSK-3beta, MDM2 and p53. |
