title: CITED2 signals through peroxisome proliferator-activated receptor-gamma to regulate death of cortical neurons after DNA damage.
abstract: DNA damage is an important initiator of neuronal apoptosis and activates signaling events not yet fully defined. Using the camptothecin-induced DNA damage model in neurons, we previously showed that cyclin D1-associated cell cycle cyclin-dependent kinases (Cdks) (Cdk4/6) and p53 activation are two major events leading to activation of the mitochondrial apoptotic pathway. With gene array analyses, we detected upregulation of Cited2, a CBP (cAMP response element-binding protein-binding protein)/p300 interacting transactivator, in response to DNA damage. This upregulation was confirmed by reverse transcription-PCR and Western blot. CITED2 was functionally important because CITED2 overexpression promotes death, whereas CITED2 deficiency protects. Cited2 upregulation is upstream of the mitochondrial death pathway (BAX, Apaf1, or cytochrome c release) and appears to be independent of p53. However, inhibition of the Cdk4 blocked Cited2 induction. The Cited2 prodeath mechanism does not involve Bmi-1 or p53. Instead, Cited2 activates peroxisome proliferator-activated receptor-gamma (PPARgamma), an activity that we demonstrate is critical for DNA damage-induced death. These results define a novel neuronal prodeath pathway in which Cdk4-mediated regulation of Cited2 activates PPARgamma and consequently caspase.
authors.affiliation: Ottawa Health Research Institute, Neuroscience Group, Ottawa, Ontario, Canada.
authors.forename: Yasmilde Rodriguez
authors.initials: YR
authors.lastname: Gonzalez
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Doreh
authors.initials: D
authors.lastname: Behzadpoor
authors.forename: Sean
authors.initials: S
authors.lastname: Cregan
authors.forename: Simon
authors.initials: S
authors.lastname: Bamforth
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002166:Camptothecin / Q000633:toxicity; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*; D014162:Transfection / Q000379:methods
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C110087:Cited2 protein, mouse; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D047495:PPAR gamma; D012097:Repressor Proteins; D045162:Thiazolidinediones; D015534:Trans-Activators; D045304:Cytochromes c; D020169:Caspases; C039671:ciglitazone; D002166:Camptothecin