Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways
Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways
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新型血管生长因子信号通路对孤儿核受体TR3转录变体的差异调节
DOI：
10.1096/fj.13-248401
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发表时间：
2014-10
期刊：
影响因子：
4.8
通讯作者：
Zeng Huiyan
中科院分区：
文献类型：
--
作者：
Zhao Shengqiang;Zhou Lei;Niu Gengming;Li Yan;Zhao Dezheng;Zeng Huiyan
血管生成是许多疾病的标志，包括癌症、缺血性心脏病、炎症等。血管内皮生长因子（vascular endothelial growth factor，VEGF）是最重要的促血管生成因子。最近，我们证明孤儿核受体TR 3（小鼠Nur 77和大鼠NGFI-B）在体外和体内肿瘤生长和VEGF-A诱导的血管生成中起关键作用。然而，介导VEGF诱导的TR 3表达的信号通路仍不完全清楚。在这里，我们报道了3种TR 3转录变体（TR 3 ‐ TV）在内皮细胞中以不同的水平表达，并受到不同的调节。在VEGF-A诱导的内皮细胞中，TR 3-TV 1的表达相对较低，而TR 3-TV 2的表达显著上调，TR 3-TV 3的表达中度上调。这些TR 3 ‐ TV的诱导动力学不同。我们还发现，包括钙-PLC-PKC-PKD 1通路、NF-κB通路和MAP激酶（ERK、p38和JNK）通路在内的几种信号通路对于VEGF-A诱导的TR 3-TV 2和TR 3-TV 3 mRNA诱导是重要的。更重要的是，我们发现VEGF-A或VEGF-E，而不是VEGF-B，也不是胎盘生长因子（PlGF），诱导胰岛素样生长因子-1受体（IGF-1 R）的磷酸化和VEGF受体2/激酶插入结构域受体（VEGFR 2/KDR）与IGF-1 R的相互作用，这介导了TR 3-TV 2的表达，但不是TR 3-TV 3。综上所述，我们证明了TR 3-TV受VEGF-A的差异调节，并确定了一种新的信号传导途径，通过该途径，VEGF-A和VEGF-E，而不是VEGF-B，也不是PlGF，诱导VEGFR 2/KDR与IGF-1 R的相互作用，导致IGF-1 R反式激活，以诱导TR 3-TV 2的高水平表达。我们的数据不仅阐明了TR 3-TV调节的信号通路，而且扩展了VEGF-A诱导血管生成的分子机制。这些研究应该允许开发用于抑制VEGF信号传导的化合物的筛选测定。赵，S.，Zhou，L.，中国科学院，Niu，G.，李，Y.，赵，D.，曾，H.，孤儿核受体TR 3转录变体通过新型血管生长因子信号通路的差异调节。FASEB J.28，4524-4533（2014）。www.fasebj.org
Angiogenesis is a hallmark of many diseases, including cancer, ischemic heart disease, inflammation, and others. It is well known that vascular endothelial growth factor (VEGF) is the most important angiogenic factor. Recently, we demonstrated that orphan nuclear receptor TR3 (mouse Nur77 and rat NGFI‐B) plays critical roles in tumor growth and angiogenesis induced by VEGF‐A in vitro and in vivo. However, the signaling pathways that mediate the expression of TR3 induced by VEGF are still not completely understood. Here we reported that 3 TR3 transcript variants (TR3‐TVs) are expressed at differential levels, and regulated differentially in endothelial cells. While the expression of TR3‐TV1 is relatively low, the expression of TR3‐TV2 is up‐regulated markedly, and the expression of TR3‐TV3 is up‐regulated moderately in endothelial cells induced by VEGF‐A. The kinetics of the induction of these TR3‐TVs is different. We also found that several signaling pathways, including calcium‐PLC‐PKC‐PKD1 pathway, NF‐κB pathway, and MAP kinase (ERK, p38, and JNK) pathways are important for VEGF‐A‐induced TR3‐TV2 and TR3‐TV3 mRNA induction. More important, we found that VEGF‐A or VEGF‐E, but not VEGF‐B, nor placenta growth factor (PlGF), induces the phosphorylation of insulin‐like growth factor‐1 receptor (IGF‐1R) and the interaction of VEGF receptor 2/kinase insert domain receptor (VEGFR2/KDR) with IGF‐1R, which mediates the expression of TR3‐TV2, but not TR3‐TV3. Taking together, we demonstrate that TR3‐TVs are differentially regulated by VEGF‐A and identify a novel signaling pathway by which VEGF‐A and VEGF‐E, but neither VEGF‐B, nor PlGF, induce the interaction of VEGFR2/ KDRwith IGF‐1R, resulting in IGF‐1R transactivation to induce the high level expression of TR3‐TV2. Our data not only elucidate the signaling pathways by which TR3‐TVs are regulated, but extend the molecular mechanism, by which VEGF‐A‐induced angiogenesis. These studies should permit the development of screening assays for compounds that inhibit VEGF signaling.—Zhao, S., Zhou, L., Niu, G., Li, Y., Zhao, D., Zeng, H., Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways. FASEB J. 28, 4524–4533 (2014). www.fasebj.org
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影响因子：
3.1
作者：
Lal, BK;Varma, S;Durán, WN
通讯作者：
Durán, WN
DOI：
--
发表时间：
1997
期刊：
The New England journal of medicine
影响因子：
--
作者：
R. Weindruch;R. S. Sohal
通讯作者：
R. Weindruch;R. S. Sohal
DOI：
10.1152/ajplung.2001.281.6.l1500
发表时间：
2001-12-01
影响因子：
4.9
作者：
Becker, PM;Verin, AD;Garcia, JGN
通讯作者：
Garcia, JGN
影响因子：
5.3
作者：
NAKAOHAYASHI, J;ITO, H;MUROTA, S
通讯作者：
MUROTA, S
影响因子：
--
作者：
R. Zetterström;L. Solomin;T. Mitsiadis;L. Olson;T. Perlmann
通讯作者：
R. Zetterström;L. Solomin;T. Mitsiadis;L. Olson;T. Perlmann