Pin1 promotes cell death in NGF-dependent neurons through a mechanism requiring c-Jun activity |
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Authors: | Barone Maria Cecilia Desouza Lynette A Freeman Robert S |
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Institution: | Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, New York, USA; Interdepartmental Graduate Program in Neuroscience, University of Rochester School of Medicine, Rochester, New York, USA |
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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 BimEL, 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 Ser63-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. |
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Keywords: | apoptosis BimEL c-Jun N-terminal kinase nerve growth factor prolyl isomerase sympathetic neuron |
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