Neuronal differentiation and protection from nitric oxide-induced apoptosis require c-Jun-dependent expression of NCAM140
Neuronal differentiation and protection from nitric oxide-induced apoptosis require c-Jun-dependent expression of NCAM140
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DOI：
10.1128/mcb.22.15.5357-5366.2002
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发表时间：
2002-08-01
影响因子：
5.3
通讯作者：
Porter, AG
中科院分区：
文献类型：
--
作者：
Feng, ZW;Li, L;Porter, AG
c-Jun是二聚体转录因子激活蛋白1（AP-1）的重要组成部分，可以调节氧化应激诱导的细胞凋亡，并与神经元分化有关，但其机制在很大程度上是未知的。我们发现，特异性抑制转录或稳定转染的cDNA编码显性负c-Jun敏感SH-SYSY神经母细胞瘤细胞（TAM-67细胞）诱导的一氧化氮（NO）供体硝普钠或SIN-1的凋亡。TAM-67细胞对神经生长因子（NGF）诱导的神经元分化也变得难治。显性阴性c-Jun消除了TAM-67细胞中140 kDa神经细胞粘附分子（NCAM 140）的表达，并显著增强了NCAM 180的表达。抑制TAM-67细胞中的c-Jun也导致NCAM 140 mRNA的量相应减少和NCAM 180 mRNA的量增加。TAM-67细胞中NCAM 140的重新表达恢复了NGF诱导的神经元分化和对NO诱导的凋亡的抵抗。我们的研究结果表明，c-jun/AP-1，通过上调NCAM 140，在神经生长因子诱导的神经元分化和抗凋亡诱导的NO在神经母细胞瘤细胞中起着重要的作用。由于NCAM 140和NCAM 180是从同一基因转录的差异剪接mRNA翻译而来，NCAM前mRNA的选择性剪接（以及因此较小的NCAM 140种类的合成）似乎受到c-Jun/AP-1的调节。
c-Jun, a crucial component of the dimeric transcription factor activating protein 1 (AP-1), can regulate apoptosis induced by oxidative stress and has been implicated in neuronal differentiation, but the mechanisms are largely unknown. We found that specific inhibition of transcription or stable transfection with cDNA encoding dominant-negative c-Jun sensitized SH-SYSY neuroblastoma cells (TAM-67 cells) to apoptosis induced by the nitric oxide (NO) donor sodium nitroprusside or SIN-1. TAM-67 cells also became refractory to nerve growth factor (NGF)-induced neuronal differentiation. Dominant-negative c-Jun abolished expression of a 140-kDa neural cell adhesion molecule (NCAM140) and dramatically enhanced the expression of NCAM180 in TAM-67 cells. Inhibition of c-Jun in TAM-67 cells also resulted in a corresponding decrease in the amount of NCAM140 mRNA and an increase in the amount of NCAM180 mRNA. Reexpression of NCAM140 in TAM-67 cells restored NGF-induced neuronal differentiation and resistance to NO-induced apoptosis. Our results show that c-jun/AP-1, through up-regulation of NCAM140, plays an important role in both NGF-induced neuronal differentiation and resistance to apoptosis induced by NO in neuroblastoma cells. As NCAM140 and NCAM180 are translated from differentially spliced mRNAs transcribed from the same gene, alternative splicing of NCAM pre-mRNA (and consequently the synthesis of the smaller NCAM140 species) appears to be regulated by c-Jun/AP-1.