title: Opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis.
abstract: The activator protein 1 (AP-1) transcription factor c-Jun is crucial for neuronal apoptosis. However, c-Jun dimerization partners and the regulation of these proteins in neuronal apoptosis remain unknown. Here we report that c-Jun-mediated neuronal apoptosis requires the concomitant activation of activating transcription factor-2 (ATF2) and downregulation of c-Fos. Furthermore, we have observed that c-Jun predominantly heterodimerizes with ATF2 and that the c-Jun/ATF2 complex promotes apoptosis by triggering ATF activity. Inhibition of c-Jun/ATF2 heterodimerization using dominant negative mutants, small hairpin RNAs, or decoy oligonucleotides was able to rescue neurons from apoptosis, whereas constitutively active ATF2 and c-Jun mutants were found to synergistically stimulate apoptosis. Bimolecular fluorescence complementation analysis confirmed that, in living neurons, c-Fos downregulation facilitates c-Jun/ATF2 heterodimerization. A chromatin immunoprecipitation assay also revealed that c-Fos expression prevents the binding of c-Jun/ATF2 heterodimers to conserved ATF sites. Moreover, the presence of c-Fos is able to suppress the expression of c-Jun/ATF2-mediated target genes and, therefore, apoptosis. Taken together, our findings provide evidence that potassium deprivation-induced neuronal apoptosis is mediated by concurrent upregulation of c-Jun/ATF2 heterodimerization and downregulation of c-Fos expression. This paradigm demonstrates opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Yuan
authors.forename: Shoufang
authors.initials: S
authors.lastname: Gong
authors.forename: Jingyan
authors.initials: J
authors.lastname: Luo
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Zheng
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.forename: Shanshan
authors.initials: S
authors.lastname: Ma
authors.forename: Jiaoli
authors.initials: J
authors.lastname: Guo
authors.forename: Ce
authors.initials: C
authors.lastname: Hu
authors.forename: Gerald
authors.initials: G
authors.lastname: Thiel
authors.forename: Charles
authors.initials: C
authors.lastname: Vinson
authors.forename: Chang-Deng
authors.initials: CD
authors.lastname: Hu
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Mingtao
authors.initials: M
authors.lastname: Li
mesh_terms: D051698:Activating Transcription Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D019281:Dimerization; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D020836:Protein Structure, Quaternary; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051698:Activating Transcription Factor 2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011188:Potassium