Angiotensin II promotes the phosphorylation of cyclic AMP-responsive element binding protein (CREB) at Ser133 through an ERK1/2-dependent mechanism
Angiotensin II promotes the phosphorylation of cyclic AMP-responsive element binding protein (CREB) at Ser133 through an ERK1/2-dependent mechanism
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DOI：
10.1046/j.1471-4159.2001.00666.x
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发表时间：
2001-12-01
影响因子：
4.7
通讯作者：
Rostas, JAP
中科院分区：
文献类型：
--
作者：
Cammarota, M;Bevilaqua, LRM;Rostas, JAP
在肾上腺髓质细胞中，血管紧张素 II (All) 调节儿茶酚胺生物合成酶的活性和 mRNA 水平，其表达被认为受到 cAMP 反应元件 (CRE) 结合蛋白 (CREB) 的控制。在本研究中，我们评估了 All 刺激对牛肾上腺嗜铬细胞 (BACC) 中 CREB Ser133 (pCREB) 磷酸化的影响。我们发现 All 产生快速且 All 1 型受体 (AT1) 依赖性的 pCREB 水平增加，这种增加被 MEK1/2 抑制剂 U0126 阻断，但不被 H-89、SB203580 或 KN-93 阻断，表明它是由细胞外调节蛋白激酶 1 和 2 (ERK1/2) 介导，而不是由 cAMP 依赖性蛋白激酶 (PKA)、p38 丝裂原激活蛋白介导。激酶 (p38MAPK) 或 Ca2+/钙调蛋白依赖性蛋白激酶 (CaMKs) 依赖性途径。凝胶迁移实验表明，pCREB 水平的增加伴随着 ERK1/2 依赖性 CRE 结合活性的上调。我们还发现 All 促进非受体酪氨酸激酶 Src 的活性快速且可逆地增加，并且抑制该酶完全阻断 All 诱导的 ERK1/2、CREB 激酶 p90RSK 和 CREB 的磷酸化。我们的数据支持这样的假设：在 BACC 中，All 通过一种需要 Src 介导的 ERK1/2 和 p90RSK 激活的机制来上调 CREB 功能。
In cells from the adrenal medulla, angiotensin II (All) regulates both the activity and mRNA levels of catecholamine biosynthetic enzymes whose expression is thought to be under the control of cAMP-responsive element (CRE) binding protein (CREB). In this study, we evaluated the effect of All stimulation on CREB phosphorylation at Ser133 (pCREB) in bovine adrenal chromaffin cells (BACC). We found that All produces a rapid and All type-1 receptor (AT1)-dependent increase in pCREB levels, which is blocked by the MEK1/2 inhibitor U0126 but not by H-89, SB203580 or KN-93, suggesting that it is mediated by the extracellular-regulated protein kinases 1 and 2 (ERK1/2) and not by cAMP-dependent protein kinase (PKA), p38 mitogen-activated protein kinase (p38MAPK) or Ca2+/calmodulin-dependent protein kinases (CaMKs) dependent pathways. Gel-shift experiments showed that the increase in pCREB levels is accompanied by an ERK1/2-dependent upregulation of CRE-binding activity, We also found that All promotes a rapid and reversible increase in the activity of the non-receptor tyrosine kinase Src and that the inhibition of this enzyme completely blocks the All-induced phosphorylation of ERK1/2, the CREB kinase p90RSK and CREB. Our data support the hypothesis that in BACC, All upregulates CREB functionality through a mechanism that requires Src-mediated activation of ERK1/2 and p90RSK.