Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53
Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53
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DOI：
10.1007/s10495-008-0185-x
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发表时间：
2008-03-01
期刊：
影响因子：
7.2
通讯作者：
Hamburger, Matthias
中科院分区：
文献类型：
--
作者：
Kueenzi, Peter;Kiefer, Sabine;Hamburger, Matthias
最近发现真菌生物碱militarinone A（MiliA）通过持续激活也参与NGF介导的分化的途径，即PI 3-K/PKB和MEK/ERK途径，刺激PC-12细胞中的神经元生长。将等浓度的MiliA应用于其他细胞如鼠神经母细胞瘤细胞系N2 a，通过凋亡诱导因子（AIF）的核转位、半胱天冬酶和c-Jun/AP-1转录因子的激活导致细胞凋亡的立即发生，而没有中间分化的表型，尽管也观察到PK B和MAPK的轻微瞬时磷酸化以及NF-κ B的激活。AIF的易位之前，在Ser 15的p53磷酸化和pifithrin α，一种已知的p53转录活性的抑制剂阻断。我们在这里表明，这两种细胞类型激活相同的途径，虽然在不同的时间尺度。这主要是由于p53的基础表达水平不同，而p53又调节AIF的表达。在PC-12细胞中，在用40 μ M MiliA长时间处理后，这些通路的连续激活首先导致p53的上调、p53的磷酸化、AIF从线粒体的释放及其易位到细胞核中。此外，还观察到c-Jun/AP-1转录因子的激活，并且PC-12细胞随后在处理后48-72小时经历凋亡。我们报告说，在不同水平上工作的类似途径能够最初形成非常不同的细胞反应。
The fungal alkaloid militarinone A (MiliA) was recently found to stimulate neuronal outgrowth in PC-12 cells by persistant activation of pathways that are also involved in NGF-mediated differentiation, namely the PI3-K/PKB and the MEK/ERK pathways. Application of equal concentrations of MiliA to other cells such as the murine neuroblastoma cell line N2a resulted in immediate onset of apoptosis by nuclear translocation of apoptosis inducing factor (AIF), activation of caspases and c-Jun/AP-1 transcription factor without an intermediate differentiated phenotype, although minor transient phosphorylation of PKB and MAPK as well as activation of NF-kappa B were also observed. Translocation of AIF was preceded by p53 phosphorylation at Ser15 and blocked by pifithrin alpha, a known inhibitor of p53-transcriptional activity. We here show that both cell types activate the same pathways albeit in different time scales. This is mainly due to contrasting basal expression levels of p53, which in turn regulates expression of AIF. In PC-12 cells, continuous activation of these pathways after prolonged treatment with 40 mu M MiliA first led to up-regulation of p53, phosphorylation of p53, release of AIF from mitochondria and its translocation into the nucleus. Additionally, also activation of the c-Jun/AP-1 transcription factor was observed, and PC-12 cells subsequently underwent apoptosis 48-72 h post-treatment. We report that similar pathways working on different levels are able to initially shape very divergent cellular responses.