Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplastic syndrome patients.
Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplastic syndrome patients.
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DOI：
10.1371/journal.pone.0061107
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kimura J
中科院分区：
文献类型：
--
作者：
Feng X;Shikama Y;Shichishima T;Noji H;Ikeda K;Ogawa K;Kimura H;Takeishi Y;Kimura J
虽然定量和定性粒细胞缺陷已被描述在骨髓增生异常综合征（MDS），在MDS的粒细胞功能障碍的潜在分子基础是在很大程度上是未知的。我们最近发现，FOS mRNA的升高抑制刺激下，MDS患者的粒细胞显着小于健康人。本研究的目的是阐明MDS中FOS诱导受损的原因。我们首先研究了FOS mRNA升高的机制，使用来自健康供体的粒细胞与翻译抑制剂embryonic一起培养。依美汀增加FOS的转录和mRNA的稳定性。抑制p38 MAPK可抑制FOS基因转录的增加，但不影响FOS mRNA的稳定性。雌激素可增加富含AU元件（ARE）的结合蛋白HuR与3′UTR含有ARE的FOS mRNA的结合，下调HuR可降低雌激素对FOS mRNA的稳定作用。接下来，我们比较了MDS患者和健康对照之间的吐根碱诱导的FOS转录和mRNA稳定性。在MDS和对照组中，embryonic引起的FOS转录速率增加相似。在没有Embryonic的情况下，两组的FOS mRNA在45分钟内衰减到初始水平的近17%。而在骨髓增生异常综合征（MDS）患者中，45 min后正常对照组FOS mRNA仍有76.7±19.8%的表达，而MDS组为37.9±25.5%（P<0.01）。据我们所知，这是第一份报告表明，在MDS粒细胞的应力诱导的FOS mRNA的稳定衰减。
Although quantitative and qualitative granulocyte defects have been described in myelodysplastic syndromes (MDS), the underlying molecular basis of granulocyte dysfunction in MDS is largely unknown. We recently found that FOS mRNA elevation under translation-inhibiting stimuli was significantly smaller in granulocytes from MDS patients than in healthy individuals. The aim of this study is to clarify the cause of the impaired FOS induction in MDS. We first examined the mechanisms of FOS mRNA elevation using granulocytes from healthy donors cultured with the translation inhibitor emetine. Emetine increased both transcription and mRNA stability of FOS. p38 MAPK inhibition abolished the emetine-induced increase of FOS transcription but did not affect FOS mRNA stabilization. The binding of an AU-rich element (ARE)-binding protein HuR to FOS mRNA containing an ARE in 3′UTR was increased by emetine, and the knockdown of HuR reduced the FOS mRNA stabilizing effect of emetine. We next compared the emetine-induced transcription and mRNA stabilization of FOS between MDS patients and healthy controls. Increased rates of FOS transcription by emetine were similar in MDS and controls. In the absence of emetine, FOS mRNA decayed to nearly 17% of initial levels in 45 min in both groups. In the presence of emetine, however, 76.7±19.8% of FOS mRNA remained after 45 min in healthy controls, versus 37.9±25.5% in MDS (P<0.01). To our knowledge, this is the first report demonstrating attenuation of stress-induced FOS mRNA stabilization in MDS granulocytes.
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