ERK5 induces ankrd1 for catecholamine biosynthesis and homeostasis in adrenal medullary cells.
ERK5 induces ankrd1 for catecholamine biosynthesis and homeostasis in adrenal medullary cells.
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DOI：
10.1016/j.cellsig.2015.12.016
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发表时间：
2016-03
影响因子：
4.8
通讯作者：
Nakahata N
中科院分区：
文献类型：
--
作者：
Obara Y;Nagasawa R;Nemoto W;Pellegrino MJ;Takahashi M;Habecker BA;Stork PJS;Ichiyanagi O;Ito H;Tomita Y;Ishii K;Nakahata N
细胞外信号调节激酶（extracellular signal-regulated kinases，ERKS）在细胞增殖、分化和基因表达中发挥重要作用。在我们之前的研究中，我们证明了ERK 5和ERK 12两者都负责大鼠嗜铬细胞瘤细胞（PC 12）中的神经突生长和酪氨酸羟化酶（TH）表达（J Biol Chem 284，23564-23573，2009）。然而，ERK 5和ERK 1/2信号在神经分化中的功能差异仍不清楚。在本研究中，我们表明，ERK 5，而不是ERK 1/2调节TH水平在大鼠交感神经元。此外，使用ERK 5和ERK 1/2特异性抑制剂在PC 1/2细胞中进行的微阵列分析鉴定了锚蛋白重复结构域1（ankrd 1）作为ERK 5依赖性和ERK 1/2非依赖性基因。在这里，我们报告了一个新的作用ERK 5/ankrd 1信号在调节TH水平和儿茶酚胺生物合成。神经生长因子对Ankrd 1 mRNA的表达具有时间和浓度依赖性。敲低ankrd 1后TH水平降低，而mRNA水平无变化，提示ankrd 1参与TH蛋白的稳定。有趣的是，通过敲低ankrd 1，TH的泛素化增强，而儿茶酚胺的生物合成减少。最后，我们研究了人肾上腺嗜铬细胞瘤中ERK 5与TH水平的关系。而TH水平与ERK 5水平在正常肾上腺髓质，ERK 5下调，TH上调，嗜铬细胞瘤，表明TH水平的调节，在肿瘤中的替代机制。两者合计，ERK 5信号是必需的儿茶酚胺生物合成在神经分化，部分诱导ankrd 1，并保持适当的TH水平。这种途径在病理条件下被破坏。
Extracellular signal-regulated kinases (ERKs) play important roles in proliferation, differentiation and gene expression. In our previous study, we demonstrated that both ERK5 and ERK1/2 were responsible for neurite outgrowth and tyrosine hydroxylase (TH) expression in rat pheochromocytoma cells (PC12) (J Biol Chem 284, 23564–23573, 2009). However, the functional differences between ERK5 and ERK1/2 signaling in neural differentiation remain unclear. In the present study, we show that ERK5, but not ERK1/2 regulates TH levels in rat sympathetic neurons. Furthermore, microarray analysis performed in PC12 cells using ERK5 and ERK1/2-specific inhibitors, identified ankyrin repeat domain 1 (ankrd1) as an ERK5-dependent and ERK1/2-independent gene. Here, we report a novel role of the ERK5/ankrd1 signaling in regulating TH levels and catecholamine biosynthesis. Ankrd1 mRNA was induced by nerve growth factor in time- and concentration-dependent manners. TH levels were reduced by ankrd1 knockdown with no changes in the mRNA levels, suggesting that ankrd1 was involved in stabilization of TH protein. Interestingly, ubiquitination of TH was enhanced and catecholamine biosynthesis was reduced by ankrd1 knockdown. Finally, we examined the relationship of ERK5 to TH levels in human adrenal pheochromocytomas. Whereas TH levels were correlated with ERK5 levels in normal adrenal medullas, ERK5 was down-regulated and TH was up-regulated in pheochromocytomas, indicating that TH levels are regulated by alternative mechanisms in tumors. Taken together, ERK5 signaling is required for catecholamine biosynthesis during neural differentiation, in part to induce ankrd1, and to maintain appropriate TH levels. This pathway is disrupted in pathological conditions.
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影响因子：
4.8
作者：
Moy, LY;Tsai, LH
通讯作者：
Tsai, LH
影响因子：
4.8
作者：
Kamakura, S;Moriguchi, T;Nishida, E
通讯作者：
Nishida, E
通过细胞外信号调节的蛋白激酶5来调节神经元存活。
影响因子：
12.4
作者：
Finegan, K. G.;Wang, X.;Lee, E-J;Robinson, A. C.;Tournier, C.
通讯作者：
Tournier, C.
影响因子：
3.5
作者：
Maeda, T;Sepulveda, J;Stewart, AFR
通讯作者：
Stewart, AFR
影响因子：
3.9
作者：
Kojic, Snezana;Nestorovic, Aleksandra;Faulkner, Georgine
通讯作者：
Faulkner, Georgine