Pin1 promotes cell death in NGF-dependent neurons through a mechanism requiring c-Jun activity
Pin1 promotes cell death in NGF-dependent neurons through a mechanism requiring c-Jun activity
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DOI：
10.1111/j.1471-4159.2008.05427.x
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发表时间：
2008-07-01
影响因子：
4.7
通讯作者：
Freeman, Robert S.
中科院分区：
文献类型：
--
作者：
Barone, Maria Cecilia;Desouza, Lynette A.;Freeman, Robert S.
被剥夺营养支持的发育中的神经元经历由c-Jun N-末端激酶（JNK）和c-Jun的激活、Bcl-2同源性3-only蛋白Bim（EL）的诱导、线粒体细胞色素c的依赖性损失和半胱天冬酶激活介导的凋亡。然而，调节这些事件的机制只有部分了解。在这里，我们表明，脯氨酰异构酶Pin 1的功能作为一个积极的调节神经元死亡通过c-Jun依赖的机制。异位Pin 1促进了NGF维持的神经元的caspase依赖性死亡，这与神经元核中Ser（63）-磷酸化c-Jun的积累有关，并且部分依赖于Bax。在NGF撤除之前下调Pin 1抑制了磷酸化c-Jun的积累，抑制了细胞色素c的释放，并显著延迟了细胞死亡。在Bim（+/+）和Bim（-/-）神经元中，Pin 1敲低抑制NGF剥夺诱导的死亡的程度相似。Pin 1基因敲除的保护作用明显大于Bim基因缺失所引起的保护作用，与c-Jun基因显性负性表达所引起的保护作用几乎相同。最后，显性负性c-Jun基因的表达在很大程度上阻断了异位Pin 1诱导的细胞死亡。
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.