title: Caspase-3 is a target gene of c-Jun:ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons.
abstract: Caspase-3, a key executor of neuronal apoptosis, is up-regulated and activated during apoptosis induced by activity deprivation in cerebellar granule neurons (CGNs). However, the transcriptional mechanism regulating caspase-3 during CGN apoptosis remains unknown. Here, we show that the caspase-3 gene is transactivated and its induction is preceded by c-Jun NH(2)-terminal kinase (JNK)/c-Jun:ATF2 pathway activation following activity deprivation in CGNs. We observed that caspase-3 induction is abolished by pharmacological inhibition of the JNK/c-Jun:ATF2 pathway. Destroying c-Jun:ATF2 heterodimers with dominant negative mutants of c-Jun and ATF2 or knockdown by small RNA interference reduced caspase-3 promoter activity and mRNA level. Furthermore, chromatin immunoprecipitation showed increased binding of c-Jun:ATF2 heterodimers to the caspase-3 promoter in response to activity deprivation in vivo. Site-directed mutagenesis of the caspase-3 promoter revealed that caspase-3 transcriptional activation depends primarily on an ATF site -233 to -225 nucleotides upstream of the start site. Taken together, these data demonstrate that caspase-3 is a target gene of c-Jun:ATF2 heterodimers during apoptosis induced by activity deprivation in CGNs.
authors: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, China.
authors: Bin
authors: B
authors: Song
authors: Bo
authors: B
authors: Xie
authors: Chong
authors: C
authors: Wang
authors: Mingtao
authors: M
authors: Li
mesh_terms: D051698:Activating Transcription Factor 2 / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism*; D002525:Cerebellar Cortex / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009433:Neural Inhibition / Q000235:genetics*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D055503:Protein Multimerization / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3