ERK1/2 is a negative regulator of homeodomain protein Arix/Phox2a.
ERK1/2 is a negative regulator of homeodomain protein Arix/Phox2a.
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ERK1/2 是同源结构域蛋白 Arix/Phox2a 的负调节因子。
DOI：
10.1111/j.1471-4159.2005.03333.x
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发表时间：
2005
影响因子：
4.7
通讯作者：
Lewis,ElaineJ
中科院分区：
文献类型：
--
作者：
Hsieh,MarleneM;Lupas,George;Rychlik,Jennifer;Dziennis,Suzan;Habecker,BethA;Lewis,ElaineJ
同源结构域蛋白 Arix/Phox2a 通过调节参与去甲肾上腺素生物合成和代谢的基因转录，在去甲肾上腺素能细胞类型的发育和维持中发挥作用。先前的研究表明，Arix/Phox2a 是一种磷蛋白，Arix/Phox2a 的磷酸化形式比去磷酸化形式表现出较差的 DNA 结合活性。在这里，我们证明 Arix/Phox2a 在 N 端反式激活域内的两个位点被细胞外信号相关激酶 (ERK)1/2 磷酸化。当用丝裂原激活蛋白激酶激酶 1 (MEK1) 抑制剂 UO126 处理细胞时，培养的 SH-SY5Y 神经母细胞瘤细胞中 Arix 的磷酸化水平会降低。使用 MEK1 抑制剂 PD98059 治疗交感神经元，会导致编码去甲肾上腺素能蛋白、多巴胺 β-羟化酶 (DBH) 和去甲肾上腺素转运蛋白 (NET) 的 mRNA 升高，但不会升高酪氨酸水解酶 (TH)。用 PD98059 处理神经母细胞瘤培养物会增加 Arix 与 DBH 和 NET 基因的相互作用，但不会增加与 TH 基因的相互作用。总之，这些结果表明 ERK1/2 对 Arix 的磷酸化抑制了其与靶基因相互作用的能力，并且表达的特异性和外部刺激的调节都是通过相同的转录因子来监测的。
The homeodomain protein Arix/Phox2a plays a role in the development and maintenance of the noradrenergic cell type by regulating the transcription of genes involved in the biosynthesis and metabolism of noradrenaline. Previous work has shown that Arix/Phox2a is a phosphoprotein, and the phosphorylated form of Arix/Phox2a exhibits poorer DNA‐binding activity than does the dephosphorylated form. Here, we demonstrate that Arix/Phox2a is phosphorylated by extracellular signal‐related kinase (ERK)1/2 at two sites within the N‐terminal transactivation domain. The phosphorylation level of Arix in cultured SH‐SY5Y neuroblastoma cells is reduced when cells are treated with the mitogen activated protein kinase kinase 1 (MEK1) inhibitor UO126. Treatment of sympathetic neurons with the MEK1 inhibitor, PD98059, results in an elevation of mRNAs encoding noradrenergic proteins, dopamine ß‐hydroxylase (DBH) and norepinephrine transporter (NET), but not tyrosine hydroyxlase (TH). Treatment of neuroblastoma cultures with PD98059 increases the interaction of Arix with DBH and NET genes, but not the TH gene. Together, these results suggest that phosphorylation of Arix by ERK1/2 inhibits its ability to interact with target genes, and that both specificity of expression and modulation by external stimuli are monitored through the same transcription factor.