title: Pin1 promotes cell death in NGF-dependent neurons through a mechanism requiring c-Jun activity.
abstract: Developing neurons deprived of trophic support undergo apoptosis mediated by activation of c-Jun N-terminal kinases (JNK) and c-Jun, induction of the Bcl-2 homology 3-only protein Bim(EL), Bax-dependent loss of mitochondrial cytochrome c, and caspase activation. However, the mechanisms that regulate each of these events are only partially understood. Here we show that the prolyl isomerase Pin1 functions as a positive regulator of neuronal death through a c-Jun-dependent mechanism. Ectopic Pin1 promoted caspase-dependent death of NGF-maintained neurons that was associated with an accumulation of Ser(63)-phosphorylated c-Jun in neuronal nuclei and was partially dependent on Bax. Downregulating Pin1 prior to NGF withdrawal suppressed the accumulation of phosphorylated c-Jun, inhibited the release of cytochrome c, and significantly delayed cell death. Pin1 knockdown inhibited NGF deprivation-induced death to a similar extent in Bim (+/+) and Bim (-/-) neurons. The protective effect of Pin1 knockdown was significantly greater than that caused by loss of Bim and nearly identical to that caused by a dominant negative form of c-Jun. Finally, cell death induced by ectopic Pin1 was largely blocked by expression of dominant negative c-Jun. These results suggest a novel mechanism by which Pin1 promotes cell death involving activation of c-Jun.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Barone
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Desouza
authors.forename: Robert S
authors.initials: RS
authors.lastname: Freeman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections / Q000379:methods; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency; D034741:RNA, Small Interfering / Q000494:pharmacology; D017783:Superior Cervical Ganglion / Q000166:cytology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D051028:bcl-2-Associated X Protein / Q000172:deficiency
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse