MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths
MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths
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DOI：
10.1091/mbc.e08-02-0159
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发表时间：
2008-08-01
影响因子：
3.3
通讯作者：
Abdellatif, Maha
中科院分区：
文献类型：
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作者：
Sayed, Danish;Rane, Shweta;Abdellatif, Maha
转录后调节因子 microRNA-21 (miR-21) 在多种癌症以及心脏肥大生长过程中表达上调。为了了解它的作用，我们在心肌细胞中过度表达它，它以细长的生长物和分支的形式揭示了一种独特类型的细胞间“连接器”。我们随后证实，miR-21 直接靶向并下调 Sprouty2 (SPRY2) 的表达，Sprouty2 是分支形态发生和神经突生长的抑制剂。我们发现β-肾上腺素能受体（β AR）刺激会诱导 miR-21 上调和 SPRY2 下调，并且同样与连接细胞分支有关。 SPRY2 的敲低再现了心肌细胞的分支形态，反之亦然，使用特定的“miRNA 擦除器”敲低 miR-21 或 SPRY2 的过表达抑制了 β AR 诱导的细胞生长。这些结构包围肌节并通过功能性间隙连接连接相邻的心肌细胞。为了确定 miR-21 功能的这一方面如何在癌细胞中翻译，我们在结肠癌 SW480 细胞中敲低了它。这导致它们的微绒毛样突起消失，并伴随着 SPRY2 依赖性细胞迁移抑制。因此，我们提出miR-21的增加通过直接靶向和下调SPRY2来增强各种类型的细胞突起的形成。
The posttranscriptional regulator, microRNA-21 (miR-21), is up-regulated in many forms of cancer, as well as during cardiac hypertrophic growth. To understand its role, we overexpressed it in cardiocytes where it revealed a unique type of cell-to-cell "linker" in the form of long slender outgrowths and branches. We subsequently confirmed that miR-21 directly targets and down-regulates the expression of Sprouty2 (SPRY2), an inhibitor of branching morphogenesis and neurite outgrowths. We found that beta-adrenergic receptor (beta AR) stimulation induces up-regulation of miR-21 and down-regulation of SPRY2 and is, likewise, associated with connecting cell branches. Knockdown of SPRY2 reproduced the branching morphology in cardiocytes, and vice versa, knockdown of miR-21 using a specific 'miRNA eraser' or overexpression of SPRY2 inhibited beta AR-induced cellular outgrowths. These structures enclose sarcomeres and connect adjacent cardiocytes through functional gap junctions. To determine how this aspect of miR-21 function translates in cancer cells, we knocked it down in colon cancer SW480 cells. This resulted in disappearance of their microvillus-like protrusions accompanied by SPRY2-dependent inhibition of cell migration. Thus, we propose that an increase in miR-21 enhances the formation of various types of cellular protrusions through directly targeting and down-regulating SPRY2.