MicroRNA-195 targets ADP-ribosylation factor-like protein 2 to induce apoptosis in human embryonic stem cell-derived neural progenitor cells.
MicroRNA-195 targets ADP-ribosylation factor-like protein 2 to induce apoptosis in human embryonic stem cell-derived neural progenitor cells.
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MicroRNA-195 靶向 ADP-核糖基化因子样蛋白 2，诱导人胚胎干细胞衍生的神经祖细胞凋亡。
DOI：
10.1038/cddis.2013.195
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发表时间：
2013-06-27
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
人胚胎干细胞来源的神经前体细胞在神经退行性疾病的细胞治疗、药物筛选和毒性试验等方面具有巨大的潜力。然而，其增殖和凋亡的分子调控，这需要在临床应用之前揭示，在很大程度上是未知的。已知microRNA miR-195在脑中表达，并参与癌细胞中的多种促凋亡或抗凋亡过程。在这里，我们定义了miR-195在两个独立的hESC系（人胚胎干细胞衍生的神经祖细胞，hESC-NPC）衍生的NPC中的促凋亡作用。miR-195在hESC-NPC中的过表达诱导广泛的凋亡性细胞死亡。一致地，全球转录微阵列分析表明，miR-195主要调控hESC-NPC中与凋亡相关的基因。在机制上，小GTP结合蛋白ADP-核糖基化因子样蛋白2（ARL 2）被鉴定为miR-195的直接靶点。在hESC-NPC中沉默ARL 2引起了类似于miR-195过表达的凋亡表型，首次揭示了ARL 2对人类NPC存活的重要作用。此外，ALR 2的强制表达可以消除miR-195过表达引起的细胞数量减少。有趣的是，我们发现百草枯，一种神经毒素，不仅诱导细胞凋亡，而且增加miR-195和减少ARL 2在hESC-NPC中的表达，表明miR-195和ARL 2可能参与神经毒素诱导的NPC凋亡。值得注意的是，抑制miR-195家族成员可以阻断神经毒素诱导的NPC凋亡。总体而言，miR-195通过直接靶向ARL 2以上下文依赖性方式调节细胞凋亡。ARL 2对人类NPC存活的关键作用以及miR-195和ARL 2与神经毒素诱导的细胞凋亡的关联的发现对于理解控制NPC存活的分子机制具有重要意义，并将有助于我们对神经发病机制的操纵。
Neural progenitor cells (NPCs) derived from human embryonic stem cells (hESCs) have great potential in cell therapy, drug screening and toxicity testing of neural degenerative diseases. However, the molecular regulation of their proliferation and apoptosis, which needs to be revealed before clinical application, is largely unknown. MicroRNA miR-195 is known to be expressed in the brain and is involved in a variety of proapoptosis or antiapoptosis processes in cancer cells. Here, we defined the proapoptotic role of miR-195 in NPCs derived from two independent hESC lines (human embryonic stem cell-derived neural progenitor cells, hESC-NPCs). Overexpression of miR-195 in hESC-NPCs induced extensive apoptotic cell death. Consistently, global transcriptional microarray analyses indicated that miR-195 primarily regulated genes associated with apoptosis in hESC-NPCs. Mechanistically, a small GTP-binding protein ADP-ribosylation factor-like protein 2 (ARL2) was identified as a direct target of miR-195. Silencing ARL2 in hESC-NPCs provoked an apoptotic phenotype resembling that of miR-195 overexpression, revealing for the first time an essential role of ARL2 for the survival of human NPCs. Moreover, forced expression of ALR2 could abolish the cell number reduction caused by miR-195 overexpression. Interestingly, we found that paraquat, a neurotoxin, not only induced apoptosis but also increased miR-195 and reduced ARL2 expression in hESC-NPCs, indicating the possible involvement of miR-195 and ARL2 in neurotoxin-induced NPC apoptosis. Notably, inhibition of miR-195 family members could block neurotoxin-induced NPC apoptosis. Collectively, miR-195 regulates cell apoptosis in a context-dependent manner through directly targeting ARL2. The finding of the critical role of ARL2 for the survival of human NPCs and association of miR-195 and ARL2 with neurotoxin-induced apoptosis have important implications for understanding molecular mechanisms that control NPC survival and would facilitate our manipulation of the neurological pathogenesis.
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影响因子：
3.7
作者：
Beghin A;Belin S;Hage-Sleiman R;Brunet Manquat S;Goddard S;Tabone E;Jordheim LP;Treilleux I;Poupon MF;Diaz JJ;Dumontet C
通讯作者：
Dumontet C
影响因子：
5.6
作者：
Finnerty JR;Wang WX;Hébert SS;Wilfred BR;Mao G;Nelson PT
通讯作者：
Nelson PT
DOI：
10.4161/cc.8.22.10033
发表时间：
2009-11-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Qi J;Yu JY;Shcherbata HR;Mathieu J;Wang AJ;Seal S;Zhou W;Stadler BM;Bourgin D;Wang L;Nelson A;Ware C;Raymond C;Lim LP;Magnus J;Ivanovska I;Diaz R;Ball A;Cleary MA;Ruohola-Baker H
通讯作者：
Ruohola-Baker H
DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
DOI：
10.1083/jcb.149.5.1087
发表时间：
2000-05-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bhamidipati A;Lewis SA;Cowan NJ
通讯作者：
Cowan NJ