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The Journal of Neuroscience, May 21, 2008, 28(21):5559-5569; doi:10.1523/JNEUROSCI.1014-08.2008

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Neurobiology of Disease
CITED2 Signals through Peroxisome Proliferator-Activated Receptor- to Regulate Death of Cortical Neurons after DNA Damage

Yasmilde Rodriguez Gonzalez,¹ Yi Zhang,¹ Doreh Behzadpoor,¹ Sean Cregan,² Simon Bamforth,³ Ruth S. Slack,¹ and David S. Park¹

¹Ottawa Health Research Institute, Neuroscience Group, Ottawa, Ontario, Canada K1H 8M5, ²Robarts Research Institute, London, Ontario, Canada N6A 5K8, and ³Department of Cardiovascular Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom

Correspondence should be addressed to David S. Park, Ottawa Health Research Institute, 451 Smyth Road, Room 2444, Ottawa, Ontario, Canada K1H 8M5. Email: dpark{at}uottawa.ca

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- (PPAR), 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 PPAR and consequently caspase.

Key words: Cited2; PPAR; Cdk4; DNA damage; cortical neurons; camptothecin

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Received Aug. 20, 2007; revised April 7, 2008; accepted April 20, 2008.

Correspondence should be addressed to David S. Park, Ottawa Health Research Institute, 451 Smyth Road, Room 2444, Ottawa, Ontario, Canada K1H 8M5. Email: dpark{at}uottawa.ca

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