Complex functions of AP-1 transcription factors in differentiation and survival of PC12 cells

c-Jun activation by mitogen-activated protein kinases has been implicated i n various cellular signal responses. We investigated how JNK and c-Jun cont ribute to neuronal differentiation, cell survival, and apoptosis. In differ entiated 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 dif ferentiated, 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 a nd 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 sti mulated by phosphorylation in the transactivation domain. In contrast, c-Ju n mutants incompetent for DNA binding or dimerization and also mutants lack ing JNK binding and phosphorylation sites that cannot elicit neuronal diffe rentiation efficiently protect PC12 cells from apoptosis. Hence, the protec tive role of c-Jun appears to be mediated by an unconventional mechanism th at is separable from its function as a classical AP-1 transcription factor.