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Molecular and Cellular Biology, July 2001, p. 4369-4378, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4369-4378.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Complex Functions of AP-1 Transcription Factors in Differentiation and Survival of PC12 Cells

Sirpa Leppä,1,2,* Minna Eriksson,1 Rainer Saffrich,3 Wilhelm Ansorge,3 and Dirk Bohmann3,*

European Molecular Biology Laboratory, D-69117 Heidelberg, Germany,3 and Haartman Institute, Department of Pathology, FIN-00014 University of Helsinki,1 and Department of Oncology, Helsinki University Central Hospital, FIN-00029 Huch,2 Finland

Received 10 November 2000/Returned for modification 10 January 2001/Accepted 28 April 2001

c-Jun activation by mitogen-activated protein kinases has been implicated in various cellular signal responses. We investigated how JNK and c-Jun contribute to neuronal differentiation, cell survival, and apoptosis. In differentiated PC12 cells, JNK signaling can induce apoptosis and c-Jun mediates this response. In contrast, we show that in PC12 cells that are not yet differentiated, the AP-1 family member ATF-2 and not c-Jun acts as an executor of apoptosis. In this context c-Jun expression protects against apoptosis and triggers neurite formation. Thus, c-Jun has opposite functions before and after neuronal differentiation. These findings suggest a model in which the balance between ATF-2 and Jun activity in PC12 cells governs the choice between differentiation towards a neuronal fate and an apoptotic program. Further analysis of c-Jun mutants showed that the differentiation response requires functional dimerization and DNA-binding domains and that it is stimulated by phosphorylation in the transactivation domain. In contrast, c-Jun mutants incompetent for DNA binding or dimerization and also mutants lacking JNK binding and phosphorylation sites that cannot elicit neuronal differentiation efficiently protect PC12 cells from apoptosis. Hence, the protective role of c-Jun appears to be mediated by an unconventional mechanism that is separable from its function as a classical AP-1 transcription factor.

* Corresponding author. Mailing address for Sirpa Leppä: Molecular and Cancer Biology Program, Biomedicum Helsinki, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 Helsingin Yliopisto, Finland. Phone: 358 9 19125606. Fax: 358 9 19125554. E-mail: sirpa.leppa{at}helsinki.fi. Present address for Dirk Bohmann: Center for Cancer Biology, Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 633, Rochester, NY 14642. Phone: (716) 273-1446. Fax: (716) 273-1450. E-mail: Dirk _Bohmann{at}urmc.rochester.edu.

Molecular and Cellular Biology, July 2001, p. 4369-4378, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4369-4378.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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