Opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis.
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.
Yuan
Zhongmin
Z
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, China.
Gong
Shoufang
S
Luo
Jingyan
J
Zheng
Zhihao
Z
Song
Bin
B
Ma
Shanshan
S
Guo
Jiaoli
J
Hu
Ce
C
Thiel
Gerald
G
Vinson
Charles
C
Hu
Chang-Deng
CD
Wang
Yizheng
Y
Li
Mingtao
M
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
D051698:Activating Transcription Factor 2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011188:Potassium