title: E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent of p53 and dependent on Bax and caspase 3.
abstract: Although B-amyloid (AB) is suggested to play an important role in Alzheimer's disease, the mechanisms that control AB-evoked toxicity are unclear. We demonstrated previously that the cell cycle-related cyclin-dependent kinase 4/6/retinoblastoma protein pathway is required for AB-mediated death. However, the downstream target(s) of this pathway are unknown. We show here that neurons lacking E2F1, a transcription factor regulated by the retinoblastoma protein, are significantly protected from death evoked by AB. Moreover, p53 deficiency does not protect neurons from death, indicating that E2F1-mediated death occurs independently of p53. Neurons protected by E2F1 deficiency have reduced Bax-dependent caspase 3-like activity. However, protection afforded by E2F1, Bax, or caspase 3 deficiency is transient. In the case of E2F1, but not with Bax or caspase 3 deficiency, delayed death is accompanied by DEVD-AFC cleavage activity. Taken together, these results demonstrate the required role of E2F1, Bax, and caspase 3 in AB evoked death, but also suggest the participation of elements independent of these apoptosis regulators.
authors.affiliation: Hoechst Marion Roussel, Neuroscience, Bridgewater, New Jersey 08807, USA.
authors.forename: A
authors.initials: A
authors.lastname: Giovanni
authors.forename: E
authors.initials: E
authors.lastname: Keramaris
authors.forename: E J
authors.initials: EJ
authors.lastname: Morris
authors.forename: S T
authors.initials: ST
authors.lastname: Hou
authors.forename: M
authors.initials: M
authors.lastname: O'Hare
authors.forename: N
authors.initials: N
authors.lastname: Dyson
authors.forename: G S
authors.initials: GS
authors.lastname: Robertson
authors.forename: R S
authors.initials: RS
authors.lastname: Slack
authors.forename: D S
authors.initials: DS
authors.lastname: Park
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004789:Enzyme Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein
chemical_list: D016229:Amyloid beta-Peptides; C533431:Arid4a protein, mouse; C494827:Bax protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003374:Coumarins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C115495:aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; D051028:bcl-2-Associated X Protein; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases