Caspase-3 is a target gene of c-Jun:ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons
Caspase-3 is a target gene of c-Jun:ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons
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Caspase-3 是小脑颗粒神经元活性剥夺诱导细胞凋亡过程中 c-Jun:ATF2 异二聚体的靶基因
DOI：
10.1016/j.neulet.2011.09.060
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发表时间：
2011-11-14
影响因子：
2.5
通讯作者：
Li, Mingtao
中科院分区：
文献类型：
--
作者：
Song, Bin;Xie, Bo;Li, Mingtao
Caspase-3是神经细胞凋亡的关键执行因子，在小脑颗粒神经元(CGN)被剥夺活性诱导的细胞凋亡过程中，Caspase-3被上调并激活。然而，caspase-3在CGN凋亡过程中的转录调控机制尚不清楚。在此，我们发现caspase-3基因被反式激活，c-jun NH(2)末端激酶(JNK)/c-jun：ATF2通路在CGN活性丧失后被激活。我们观察到，通过药物抑制JNK/c-Jun：ATF2通路，caspase-3的诱导被取消。用c-jun和ATF2的显性负突变破坏c-jun：ATF2异源二聚体，或用小RNA干扰敲除c-jun：ATF2异源二聚体，均可降低caspase-3启动子活性和mRNA水平。此外，染色质免疫沉淀显示c-jun：ATF2异源二聚体与caspase-3启动子的结合增加，以响应体内活性丧失。Caspase-3启动子的定点突变表明，caspase-3的转录激活主要依赖于起始位点上游的ATF位点-233到-225核苷酸。综上所述，这些结果表明caspase-3是c-jun：ATF2异源二聚体在活性剥夺诱导的CGN细胞凋亡过程中的靶基因。(C)2011爱思唯尔爱尔兰有限公司。保留所有权利。
Caspase-3, a key executor of neuronal apoptosis, is up-regulated and activated during apoptosis induced by activity deprivation in cerebellar granule neurons (CGNs). However, the transcriptional mechanism regulating caspase-3 during CGN apoptosis remains unknown. Here, we show that the caspase-3 gene is transactivated and its induction is preceded by c-Jun NH(2)-terminal kinase (JNK)/c-Jun:ATF2 pathway activation following activity deprivation in CGNs. We observed that caspase-3 induction is abolished by pharmacological inhibition of the JNK/c-Jun:ATF2 pathway. Destroying c-Jun:ATF2 heterodimers with dominant negative mutants of c-Jun and ATF2 or knockdown by small RNA interference reduced caspase-3 promoter activity and mRNA level. Furthermore, chromatin immunoprecipitation showed increased binding of c-Jun:ATF2 heterodimers to the caspase-3 promoter in response to activity deprivation in vivo. Site-directed mutagenesis of the caspase-3 promoter revealed that caspase-3 transcriptional activation depends primarily on an ATF site -233 to -225 nucleotides upstream of the start site. Taken together, these data demonstrate that caspase-3 is a target gene of c-Jun:ATF2 heterodimers during apoptosis induced by activity deprivation in CGNs. (C) 2011 Elsevier Ireland Ltd. All rights reserved.