The NR4A orphan nuclear receptor NOR1 is induced by platelet-derived growth factor and mediates vascular smooth muscle cell proliferation
The NR4A orphan nuclear receptor NOR1 is induced by platelet-derived growth factor and mediates vascular smooth muscle cell proliferation
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DOI：
10.1074/jbc.m603436200
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发表时间：
2006-11-03
影响因子：
4.8
通讯作者：
Bruemmer, Dennis
中科院分区：
文献类型：
--
作者：
Nomiyama, Takashi;Nakamachi, Takafumi;Bruemmer, Dennis
核激素受体超家族成员作为心血管疾病中炎症和增殖的关键转录调节因子发挥作用。除了配体依赖性过氧化物酶体增殖物激活受体和肝X受体外，该转录因子家族还包括大量孤儿受体，它们在血管疾病中的作用仍有待研究。神经元源性孤儿受体-1（NOR 1）属于配体非依赖性NR 4A亚家族，与细胞增殖、分化和凋亡有关。在这项研究中，我们证明了NOR 1在人动脉粥样硬化病变的血管平滑肌细胞（SMC）中的表达。在血小板源性生长因子（PDGF）的促有丝分裂刺激下，SMC通过ERK-MAPK依赖的信号通路快速表达NOR 1。5 '-缺失分析、定点突变和反式激活实验证明，PDGF诱导的NOR 1表达是通过NOR 1启动子的cAMP反应元件结合蛋白（CREB）依赖性反式激活介导的。因此，短干扰RNA介导的CREB耗竭废除PDGF诱导的SMC NOR 1表达。此外，PDGF诱导CREB的Ser-133磷酸化，随后与内源性NOR 1启动子的CRE位点结合。功能分析表明，PDGF诱导NOR 1反式激活其共识NGFI-B反应元件（NBRE）在SMC。我们最后证明，从NOR 1缺陷小鼠分离的SMC表现出细胞增殖减少和表征细胞周期蛋白D1和D2作为NOR 1的靶基因在SMC。这些实验表明，PDGF诱导的NOR 1在SMC中的转录是通过CREB依赖的NOR 1启动子的反式激活介导的，并进一步证明NOR 1作为SMC增殖的关键转录调节因子发挥作用。
Members of the nuclear hormone receptor superfamily function as key transcriptional regulators of inflammation and proliferation in cardiovascular diseases. In addition to the ligand-dependent peroxisome proliferator-activated receptors and liver X receptors, this family of transcription factors includes a large number of orphan receptors, and their role in vascular diseases remains to be investigated. The neuron-derived orphan receptor-1 (NOR1) belongs to the ligand-independent NR4A subfamily, which has been implicated in cell proliferation, differentiation, and apoptosis. In this study, we demonstrate NOR1 expressionin vascular smooth muscle cells (SMC) of human atherosclerotic lesions. In response to mitogenic stimulation with platelet-derived growth factor ( PDGF), SMC rapidly express NOR1 through an ERK-MAPK-dependent signaling pathway. 5'- Deletion analysis, site-directed mutagenesis, and transactivation experiments demonstrate that PDGF-induced NOR1 expression is mediated through a cAMP-response element-binding protein (CREB)-dependent transactivation of the NOR1 promoter. Consequently, short interfering RNA mediated depletion of CREB abolished PDGF-induced NOR1 expression in SMC. Furthermore, PDGF induced Ser-133 phosphorylation of CREB and subsequent binding to the CRE sites of the endogenous NOR1 promoter. Functional analysis demonstrated that PDGF induces NOR1 transactivation of its consensus NGFI-B-response elements (NBRE) in SMC. We finally demonstrate that SMC isolated from NOR1-deficient mice exhibit decreased cell proliferation and characterize cyclin D1 and D2 as NOR1 target genes in SMC. These experiments indicate that PDGF-induced NOR1 transcription in SMC is mediated through CREB-dependent transactivation of the NOR1 promoter and further demonstrate that NOR1 functions as a key transcriptional regulator of SMC proliferation.