cytochrome-c-t and ciglitazone

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.

Topics: Anilides; Animals; Camptothecin; Caspases; Cell Death; Cells, Cultured; Cerebral Cortex; Cytochromes c; DNA Damage; DNA-Binding Proteins; Embryo, Mammalian; Enzyme Inhibitors; Gene Expression Regulation; Immunoprecipitation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; PPAR gamma; Repressor Proteins; Signal Transduction; Thiazolidinediones; Time Factors; Trans-Activators; Transfection