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Molecular and Cellular Biology, May 2009, p. 2431-2442, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01344-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Opposing Roles for ATF2 and c-Fos in c-Jun-Mediated Neuronal Apoptosis{triangledown}

Zhongmin Yuan,1,2,# Shoufang Gong,1,2,# Jingyan Luo,1,2,# Zhihao Zheng,1,2 Bin Song,1,2 Shanshan Ma,1,2 Jiaoli Guo,1,2 Ce Hu,1,2 Gerald Thiel,3 Charles Vinson,4 Chang-Deng Hu,5 Yizheng Wang,6 and Mingtao Li1,2*

Department of Pharmacology,1 Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, China,2 Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, Homburg D-66421, Germany,3 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,4 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907,5 Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Science, Shanghai 200031, China6

Received 23 August 2008/ Returned for modification 19 September 2008/ Accepted 10 February 2009

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.

* Corresponding author. Mailing address: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, China. Phone: 86-20-87330161. Fax: 86-20-87331653. E-mail: limt{at}mail.sysu.edu.cn

{triangledown} Published ahead of print on 2 March 2009.

# These authors contributed equally to this work.

Molecular and Cellular Biology, May 2009, p. 2431-2442, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01344-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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