Dynamic regulation of estrogen receptor-α isoform expression in the mouse fallopian tube:: mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors
Dynamic regulation of estrogen receptor-α isoform expression in the mouse fallopian tube:: mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors
复制标题
DOI：
10.1152/ajpendo.00384.2007
复制
发表时间：
2007-11-01
影响因子：
5.1
通讯作者：
Billig, Hakan
中科院分区：
文献类型：
--
作者：
Shao, Ruijin;Egecioglu, Emil;Billig, Hakan
雌激素受体 (ER) 是核受体超家族的成员，参与输卵管功能的调节（即增强蛋白质分泌、输卵管液的形成和配子运输的调节）。然而，这些过程背后的 ER 亚型介导机制尚未完全阐明。最近，我们在大鼠输卵管中发现了 ER β 的表达和定位，表明 ER β 的潜在生物学功能与钙依赖性纤毛跳动相关。在这里，我们首次深入了解研究较少的 ER α 亚型，该亚型介导体内雌激素依赖性 IGF 的产生和分泌。首先，蛋白质印迹研究表明，小鼠输卵管中表达了三种 ER α 亚型。随后的免疫组织化学分析表明，ER α 在所有细胞类型中均检测到，而 ER β 主要位于纤毛上皮细胞中。其次，通过 E-2 或 PPT（一种 ER α 激动剂）治疗，小鼠输卵管中 ER α 亚型水平显着下调，且呈时间依赖性。第三，ER 拮抗剂 ICI 182,780 的存在阻断了 E-2 或 PPT 诱导的小鼠输卵管 ER α 亚型表达的下调。然而，仅在壶腹部上皮细胞中检测到 ICI 182,780 治疗后 ER α 免疫反应性的改变。第四，发现 ER α 同工型表达的变化与 E-2 对小鼠输卵管组织和液体中输卵管生长、蛋白质合成和分泌的多种影响有关。特别是，E-2 对 IGF-I 和 IGF-II 蛋白水平表现出正向调节作用。最后，使用生长激素受体 (GHR) 基因破坏的小鼠，我们发现 E-2 对 IGF 产生的调节独立于体内小鼠输卵管中 GH 诱导的 GHR 信号传导。这些数据与我们实验室之前的研究一起表明，雌激素激动剂的长期作用通过刺激 ER α 来促进小鼠输卵管上皮细胞和输卵管液中 IGF 的合成和分泌。
Estrogen receptors (ERs) are members of the nuclear receptor superfamily and are involved in regulation of fallopian tube functions (i.e., enhancement of protein secretion, formation of tubal fluid, and regulation of gamete transport). However, the ER subtype-mediated mechanisms underlying these processes have not been completely clarified. Recently, we identified ER beta expression and localization in rat fallopian tubes, suggesting a potential biological function of ER beta related to calcium-dependent ciliated beating. Here we provide for the first time insight into the less studied ER alpha isoforms, which mediate estrogen-dependent production and secretion of IGFs in vivo. First, Western blot studies revealed that three ER alpha isoforms were expressed in mouse fallopian tubes. Subsequent immunohistochemical analysis showed that ER alpha was detected in all cell types, whereas ER beta was mainly localized in ciliated epithelial cells. Second, ER alpha isoform levels were dramatically down-regulated in mouse fallopian tubes by treatment with E-2 or PPT, an ER alpha agonist, in a time-dependent manner. Third, the presence of ICI 182,780, an ER antagonist, blocked the E-2-or PPT-induced down-regulation of tubal ER alpha isoform expression in mice. However, alteration of ER alpha immunoreactivity following ICI 182,780 treatment was only detected in epithelial cells of the ampullary region. Fourth, changes in ER alpha isoform expression were found to be coupled to multiple E-2 effects on tubal growth, protein synthesis, and secretion in mouse fallopian tube tissues and fluid. In particular, E-2 exhibited positive regulation of IGF-I and IGF-II protein levels. Finally, using growth hormone receptor (GHR) gene-disrupted mice, we showed that regulation by E-2 of IGF production was independent of GH-induced GHR signaling in mouse fallopian tubes in vivo. These data, together with previous studies from our laboratory, suggest that the long-term effects of estrogen agonist promote IGF synthesis and secretion in mouse tubal epithelial cells and fallopian tube fluid via stimulation of ER alpha.