MicroRNA modulation of megakaryoblast fate involves cholinergic signaling
MicroRNA modulation of megakaryoblast fate involves cholinergic signaling
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DOI：
10.1016/j.leukres.2005.09.005
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发表时间：
2006-05-01
影响因子：
2.7
通讯作者：
Soreq, H
中科院分区：
文献类型：
--
作者：
Guimaraes-Sternberg, C;Meerson, A;Soreq, H
microRNAs（miRNAs）是一类在细胞命运决定中具有多种作用的小分子调控RNA。调节细胞miRNA水平的过程仍然不清楚，并且还没有实验性的寡核苷酸工具来容易地模拟它们的作用。在这里，我们报告了毒胡萝卜素诱导的细胞内Ca++释放抑制人promega-Meg-01细胞中的pre-miR-181 a水平，诱导分化相关的核内复制和caspase-3激活，并用AChE-R、AChE、PKC和PKA抑制剂替代乙酰胆碱酯酶3'剪接变体AChE-S，所有这些都减弱了pre-miR-181 a的下降和诱导的分化。AChmiON是一种模拟miR-181 a序列的合成23-mer 2 '-羟甲基化寡核苷酸，可阻断钙诱导的分化，同时提高细胞前体miR-181 a水平并诱导DNA片段化和细胞死亡。此外，当添加到RW 264.7巨噬细胞中时，100 nM的AChmiON诱导一氧化氮产生，其效率接近细菌内毒素的效率，这也证明了在血液产生的单核细胞/巨噬细胞中的生理相关活性。通过AChE、PKC和PKA级联的造血miR-181 a水平的应激诱导的调节表明使用miRNA模拟物将造血肿瘤细胞的命运转向分化和/或凋亡。(C)2005爱思唯尔有限公司保留所有权利。
MicroRNAs (miRNAs) are abundant small regulatory RNAs with multiple roles in cell fate determination. The processes regulating cellular miRNA levels are still unclear and experimental oligonucleotide tools to readily mimic their effects are not yet available. Here, we report that thapsigargin-induced intracellular Ca++ release suppressed pre-miR-181a levels in human promegakaryotic Meg-01 cells, induced differentiation-associated nuclear endoreduplication and caspase-3 activation and replaced the acetylcholinesterase 3' splice variant AChE-S with AChE-R, AChE, PKC and PKA inhibitors all attenuated the pre-miR-181a decline and the induced differentiation. AChmiON, a synthetic 23-mer 2'-oxymethylated oligonucleotide mimicking the miR-181a sequence, blocked the calcium-induced differentiation while elevating cellular pre-miR-181a levels and inducing DNA fragmentation and cell death. Moreover, when added to RW 264.7 macrophages, AChmiON at 100 nM induced nitric oxide production with efficiency close to that of bacterial endotoxin, demonstrating physiologically relevant activities also in blood-born monocytes/macrophagcs. The stress-induced modulation of hematopoietic miR-181a levels through AChE, PKC and PKA cascade(s) suggests using miRNA mimics for diverting the fate of hematopoietic tumor cells towards differentiation and/or apoptosis. (C) 2005 Elsevier Ltd. All rights reserved.