CITED2 signals through peroxisome proliferator-activated receptor-gamma to regulate death of cortical neurons after DNA damage

• Published in: The Journal of neuroscience 2008-05, Vol.28 (21), p.5559-5569
• Main Authors: Gonzalez, Yasmilde Rodriguez, Zhang, Yi, Behzadpoor, Doreh, Cregan, Sean, Bamforth, Simon, Slack, Ruth S, Park, David S
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Animals; Camptothecin - toxicity; Caspases - metabolism; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Cerebral Cortex - cytology; Cytochromes c - metabolism; DNA Damage - drug effects; DNA Damage - physiology; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - physiology; Embryo, Mammalian; Enzyme Inhibitors - toxicity; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Immunoprecipitation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons - physiology; PPAR gamma - physiology; Repressor Proteins - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Thiazolidinediones - pharmacology; Time Factors; Trans-Activators - deficiency; Trans-Activators - physiology; Transfection - methods
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1014-08.2008

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.