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

J Neurosci. 2008 May 21;28(21):5559-69. doi: 10.1523/JNEUROSCI.1014-08.2008.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Cited2 protein, mouse
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • PPAR gamma
  • Repressor Proteins
  • Thiazolidinediones
  • Trans-Activators
  • Cytochromes c
  • Caspases
  • ciglitazone
  • Camptothecin