ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis
ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis
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DOI：
10.1073/pnas.1412172111
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发表时间：
2014-12-23
影响因子：
11.1
通讯作者：
Hla, Timothy
中科院分区：
文献类型：
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作者：
Chang, Sung-Hee;Elemento, Olivier;Hla, Timothy
转录后RNA调控在决定细胞表型的可塑性方面是重要的。然而，RNA结合蛋白（RBP）如何影响细胞行为的机制知之甚少。我们在这里显示，RBP胚胎致死异常视觉样1（ELAVL 1，也称为HuR）调节真核翻译起始因子4 E核输入因子1（Eif 4 enif 1）的选择性剪接，Eif 4 enif 1编码真核翻译起始因子4 E转运蛋白（4 E-T），并抑制加帽mRNA的表达。在缺乏ELAVL 1的情况下，Eif 4 enif 1的外显子11的跳跃形成稳定的短同种型4 E-T-s。这种选择性剪接事件导致RNA加工体（PB）的形成、血管生成mRNA的更新增强以及血管内皮细胞的发芽行为受到抑制。此外，内皮特异性Elavl 1基因敲除小鼠表现出后肢缺血后血管重建减少和癌基因诱导的乳腺癌中的肿瘤血管生成，分别导致血流和肿瘤生长减弱。ELAVL 1调节Eif 4 enif 1的选择性剪接导致PB和mRNA周转的形成增强，构成了一种新的转录后机制，对病理性血管生成至关重要。
Posttranscriptional RNA regulation is important in determining the plasticity of cellular phenotypes. However, mechanisms of how RNA binding proteins (RBPs) influence cellular behavior are poorly understood. We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs. In the absence of ELAVL1, skipping of exon 11 of Eif4enif1 forms the stable, short isoform, 4E-T-s. This alternative splicing event results in the formation of RNA processing bodies (PBs), enhanced turnover of angiogenic mRNAs, and suppressed sprouting behavior of vascular endothelial cells. Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. ELAVL1-regulated alternative splicing of Eif4enif1 leading to enhanced formation of PB and mRNA turnover constitutes a novel posttranscriptional mechanism critical for pathological angiogenesis.