The transcription factor E2F1 promotes dopamine-evoked neuronal apoptosis by a mechanism independent of transcriptional activation
The transcription factor E2F1 promotes dopamine-evoked neuronal apoptosis by a mechanism independent of transcriptional activation
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DOI：
10.1046/j.1471-4159.2001.00402.x
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发表时间：
2001-07-01
影响因子：
4.7
通讯作者：
MacManus, JP
中科院分区：
文献类型：
--
作者：
Hou, ST;Cowan, E;MacManus, JP
E2F1转录因子在促进神经细胞凋亡中起着重要作用，但目前还不清楚E2F1是如何做到这一点的。我们发现E2F1参与了多巴胺(DA)诱导的小脑颗粒神经元(CGN)的凋亡，与对照组相比，E2F1-/-CGN和表达反义E2F1基因的CGN明显免受DA的毒性，神经元保护伴随着caspase3活性的显著降低。E2F1介导的神经细胞凋亡不需要激活基因转录，因为：(1)缺乏反式激活结构域的E2F1或其突变体的异位表达诱导了神经元的凋亡，而缺乏DNA结合结构域的E2F1突变体则不诱导；(2)在所有这些条件下，已知的E2F1靶基因包括细胞周期蛋白A、cdc2和p19(Arf)均未被诱导；(3)DA诱导的神经细胞凋亡与E2F1基因的上调有关，但与其靶基因的转录无关。最后，E2F1介导的神经细胞凋亡与核因子-kappaB DNA结合活性降低有关。综上所述，这些数据表明，E2F1通过一种独立于基因反式激活的机制促进DA诱导的caspase3依赖的神经元凋亡，这可能是通过抑制包括NF-kappaB在内的抗凋亡基因来实现的。
The E2F1 transcription factor plays an important role in promoting neuronal apoptosis; however, it is not clear how E2F1 does this. Here we show that E2F1 is involved in dopamine (DA)-evoked apoptosis in cerebellar granule neurons (CGNs), E2F1 -/- CGNs and CGNs expressing an antisense E2F1 cDNA were significantly protected from DA-toxicity relative to controls, The neuronal protection was accompanied by significantly reduced caspase 3 activity. E2F1-mediated neuronal apoptosis did not require activation of gene transcription because: (1) ectopic expression of E2F1 or its mutants lacking the transactivation domain induced neuronal apoptosis, whereas an E2F1 mutant lacking the DNA-binding domain did not; (2) under all of these conditions, known E2F1 target genes including cyclin A, cdc2 and p19(ARF) were not induced; and (3) DA-evoked neuronal apoptosis was associated with up-regulated E2F1, but not transcription of its target genes. Finally, E2F1-mediated neuronal apoptosis was associated with reduced nuclear factor (NF)-kappaB DNA-binding activity. Taken together, these data suggest that E2F1 promotes DA-evoked caspase 3-dependent neuronal apoptosis by a mechanism independent of gene transactivation, and this may possibly occur through inhibition of anti-apoptotic genes including NF-kappaB.