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Pin1 promotes cell death in NGF‐dependent neurons through a mechanism requiring c‐Jun activity
Author(s) -
Barone Maria Cecilia,
Desouza Lynette A.,
Freeman Robert S.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05427.x
Subject(s) - pin1 , c jun , programmed cell death , peptidylprolyl isomerase , gene knockdown , microbiology and biotechnology , apoptosis , cytochrome c , biology , phosphorylation , ectopic expression , kinase , caspase , nerve growth factor , chemistry , cancer research , mitochondrion , cell culture , biochemistry , transcription factor , isomerase , gene , receptor , genetics
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.