A new γ-interferon-inducible promoter and splice variants of an anti-angiogenic human tRNA synthetase
A new γ-interferon-inducible promoter and splice variants of an anti-angiogenic human tRNA synthetase
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DOI：
10.1093/nar/gkh240
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发表时间：
2004-01-01
影响因子：
14.9
通讯作者：
Schimmel, P
中科院分区：
文献类型：
--
作者：
Liu, JM;Shue, E;Schimmel, P
两种形式的人类色氨酸- trna合成酶（trpr）在体内通过不同的mRNA剪接产生。全长trpr和迷你trpr这两种形式都具有催化活性，但其区别在于迷你trpr具有显著的抗增殖和抗血管生成活性。在这里，我们描述了人类TrpRS mRNA的两个新的剪接变体。它们的产生受到γ -干扰素（ifn - γ）的强烈调节，γ -干扰素是一种抗增殖细胞因子，已知可刺激其他抗血管生成因子的表达。一种新的ifn - γ敏感启动子被证明可以驱动这些剪接变体的产生。在人类内皮细胞中，新发现的启动子和先前报道的启动子都被证明对ifn - γ有特异性反应，而对其他细胞因子如肿瘤坏死因子- α、转化生长因子- β、白细胞介素-4或促红细胞生成素没有反应。此外，这两个启动子都受到“下游”干扰素调节因子1的刺激，而“下游”干扰素调节因子1反过来又受到“上游”信号换能器和转录1 α亚基激活因子的调节。因此，串联启动子提供了一个双重系统来调节人类trpr在体内的表达和选择性剪接。
Two forms of human tryptophanyl-tRNA synthetase (TrpRS) are produced in vivo through alternative mRNA splicing. The two forms, full-length TrpRS and mini TrpRS, are catalytically active, but are distinguished by the striking anti-proliferative and anti-angiogenic activity specific to mini TrpRS. Here we describe two new splice variants of human TrpRS mRNA. Their production was strongly regulated by gamma-interferon (IFN-gamma), an anti-proliferative cytokine known to stimulate the expression of other anti-angiogenic factors. A new IFN-gamma-sensitive promoter was demonstrated to drive production of these splice variants. In human endothelial cells, both the newly discovered and a previously reported promoter were shown to respond specifically to IFN-gamma and not to other cytokines such as tumor necrosis factor-alpha, transforming growth factor-beta, interleukin-4 or erythropoietin. In addition, both promoters were stimulated by the 'downstream' interferon regulatory factor 1 that, in turn, is known to be regulated by the 'upstream' signal transducer and activator of transcription 1alpha subunit. Thus, the tandem promoters provide a dual system to regulate expression and alternative splicing of human TrpRS in vivo.