cep-11004 and Potassium-Deficiency

In eukaryotes, mitochondria are critical for cellular bioenergetics and mediating apoptosis. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is an important regulator of mitochondrial biogenesis and function. However, the role of PGC-1alpha in neuronal apoptosis and its regulation by apoptotic pathway are still unknown. We demonstrated that PGC-1alpha expression was down-regulated in cerebellar granule neurons(CGNs) after activation of the JNK/c-Jun pathway by potassium deprivation. Overexpression of PGC-1alpha partially protected CGNs from potassium deprivation-induced apoptosis. JNK-specific inhibitors, SP600125 and CEP11004, partially blocked the inhibitory effects of JNK on PGC-1alpha expression and its promoter activity. Furthermore, ChIP assays revealed that c-Jun was able to bind to the CRE site (-188 to -180) in the PGC-1alpha promoter. In conclusion, these results suggest that down-expression of PGC-1alpha partially mediated by activation of JNK/c-Jun may be through the binding of c-Jun to the CRE site in the PGC-1alpha promoter, and it might be involved in potassium deprivation-induced apoptosis in CGNs.

Topics: Animals; Anthracenes; Apoptosis; Carbazoles; Cells, Cultured; Cerebellum; Down-Regulation; Enzyme Inhibitors; JNK Mitogen-Activated Protein Kinases; Neurons; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Potassium; Potassium Deficiency; Promoter Regions, Genetic; Protein Binding; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins; Transcription Factors