A novel miR-200b-3p/p38IP pair regulates monocyte/macrophage differentiation.
A novel miR-200b-3p/p38IP pair regulates monocyte/macrophage differentiation.
复制标题
新型 miR-200b-3p/p38IP 对调节单核细胞/巨噬细胞分化。
DOI：
10.1038/celldisc.2015.43
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发表时间：
2016
期刊：
影响因子：
33.5
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Yu X;Wang QL;Li YF;Wang XD;Xu A;Li Y
单核细胞/巨噬细胞分化代表造血的主要分支，并且是免疫应答中的中心事件，但其分子机制尚未完全阐明。在这里，我们表明，p38丝裂原活化蛋白激酶（MAPK）相互作用蛋白（p38 IP）在体外单核细胞/巨噬细胞分化过程中下调。p38 IP的过表达可阻止单核/巨噬细胞的分化，而RNA干扰正向敲低p38 IP则可诱导单核/巨噬细胞G1/S期阻滞，促进单核/巨噬细胞的分化和成熟。此外，我们发现miR-200 b-3 p在单核/巨噬细胞分化过程中表达上调，并通过与p38 IP mRNA的3′端非翻译区结合介导p38 IP的下调。miR-200 b-3 p模拟物的过表达类似于p38 IP敲低的效果，而miR-200 b-3 p抑制剂通过增强p38 IP表达来阻断单核细胞/巨噬细胞分化。进一步的蛋白质印迹分析显示，p38 IP下调增强p38 MAPK的活性和随后的细胞周期蛋白依赖性激酶抑制剂p21的积累，从而促进G1/S阻滞和单核/巨噬细胞分化。此外，由p38 IP下调引起的GCN 5乙酰转移酶的下降是必需的，但对于单核细胞/巨噬细胞分化是不够的。这项研究证明了p38 IP和一种新的miR-200 b-3 p/p38 IP对在调节单核细胞/巨噬细胞分化中的新作用。
Monocyte/macrophage differentiation represents a major branch of hematopoiesis and is a central event in the immune response, but the molecular mechanisms underlying are not fully delineated. Here we show that p38 mitogen-activated protein kinase (MAPK) interacting protein (p38IP) is downregulated during monocyte/macrophage differentiation in vitro. Overexpression of p38IP halted monocyte/macrophage differentiation, whereas forward knockdown of p38IP by RNA interference induced G1/S arrest and promoted monocyte differentiation into macrophages and the maturation of macrophages as well. Moreover, we found that miR-200b-3p was upregulated during monocyte/macrophage differentiation and mediated the downregulation of p38IP by binding to the 3′ untranslated terminal region of p38IP mRNA. Overexpression of a miR-200b-3p mimic resembled the effect of p38IP knockdown, whereas a miR-200b-3p inhibitor blocked monocyte/macrophage differentiation by enhancing p38IP expression. Further western blotting analysis revealed that p38IP downregulation enhanced the activity of p38 MAPK and the subsequent accumulation of cyclin-dependent kinase inhibitor p21, thus promoting G1/S arrest and monocyte/macrophage differentiation. Moreover, the decline of GCN5 acetyltransferase caused by p38IP downregulation was required but was not sufficient for monocyte/macrophage differentiation. This study demonstrated a new role for p38IP and a novel miR-200b-3p/p38IP pair in the regulation of monocyte/macrophage differentiation.