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.