Molecular mechanisms of neuronal cell death: implications for nuclear factors responding to cAMP and phorbol esters.
Chronic treatment with calcium ionophore A23187 in NGF-differentiated cells results in cell death that is time- and concentration-dependent. Additionally, PC12 cells codifferentiated with NGF and dBcAMP become dependent on these factors for survival and undergo apoptosis when both factors are withdrawn. We show that in both cases there is a prolonged induction of c-Fos which correlates with cell death. Its continual activation in PC12 cells overexpressing c-FosER results in caspase-3 cleavage and rapid cell death. Specific phosphorylation of CREB/CREM(tau) transactivators or their binding to CRE of c-fos was observed. Our results indicate that prolonged c-Fos induction activates p53. There is increased nuclear localization of p53, p21 and Bax levels are induced in NGF/dBcAMP-deprived c-FosER cells, and dominant negative p53 inhibits cell death induced either by serum deprivation or by c-Fos. Overall these data implicate AP-1 as a nuclear target of signal transduction pathways which plays a role in the activation of apoptosis.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002490:Central Nervous System / Q000254:growth & development* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010703:Phorbol Esters / Q000494:pharmacology; D011485:Protein Binding / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D007476:Ionophores; D009414:Nerve Growth Factors; D010703:Phorbol Esters; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000242:Cyclic AMP; D002118:Calcium