| First Author | Smith RA | Year | 2003 |
| Journal | Brain Res Mol Brain Res | Volume | 116 |
| Issue | 1-2 | Pages | 70-9 |
| PubMed ID | 12941462 | Mgi Jnum | J:85607 |
| Mgi Id | MGI:2675803 | Doi | 10.1016/s0169-328x(03)00253-5 |
| Citation | Smith RA, et al. (2003) Involvement of the transcription factor E2F1/Rb in kainic acid-induced death of murine cerebellar granule cells. Brain Res Mol Brain Res 116(1-2):70-9 |
| abstractText | The full mechanisms underlying neuronal death following excitotoxic insult remain unclear, despite many in vivo and in vitro studies. Recent work has focused on various signaling molecules and pathways, normally strictly regulated, that can trigger death if perturbed. The transcription factor, E2F1 is pivotal in controlling cell death under stress situations. The current study aimed to investigate the role of this transcription factor in modulating neuronal death following kainic acid (KA) treatment of cultured mouse cerebellar granule cells (CGCs). KA-induced death of CGCs was attenuated by the selective KA/AMPA receptor antagonist CNQX, but not MK-801. Such neuronal death was caspase-3-independent and did not activate many known death genes, such as Fas receptor, caspase-8 and p38. However, hyperphosphorylation of Rb showed a transient increase which may lead to activation of E2F1. Indeed E2F1 +/+ and -/- CGCs showed a differential response to KA-mediated toxicity, in that E2F1 -/- neurons were significantly less susceptible to KA compared to E2F1 +/+ neurons, albeit both E2F1 +/+ and -/- neurons expressed similar levels of KA receptors and responded similarly to kainate antagonist, CNQX. Using selective inhibitors to CDKs, such as olomoucine, roscovitine and flavopiridol, and the inhibitor SB203580 to p38 MAPK, we ruled out the possibility that Rb inactivation through hyperphosphorylation was due to either upstream kinases. Therefore activation of Rb/E2F1 pathway appears to involve novel interactions yet to be elucidated. |
