Transactivation of the Epidermal Growth Factor Receptor Is Involved in the Lutropin Receptor-Mediated Down-Regulation of Ovarian Aromatase Expression in Vivo
Transactivation of the Epidermal Growth Factor Receptor Is Involved in the Lutropin Receptor-Mediated Down-Regulation of Ovarian Aromatase Expression in Vivo
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DOI：
10.1210/me.2009-0450
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发表时间：
2010-03-01
影响因子：
--
通讯作者：
Ascoli, Mario
中科院分区：
文献类型：
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作者：
Andric, Nebojsa;Thomas, Mika;Ascoli, Mario
卵巢卵泡的发育和分化以芳香化酶（Cyp19a1）表达的显著变化为特征。在排卵前卵泡中，促卵泡激素（FSH）受体的激活会增加芳香化酶的表达，直至促黄体生成素（LH）峰使其降低。在此我们提供体内证据表明，LH峰对Cyp19a1的下调需要通过表皮生长因子受体（EGFR）的有效信号传导。在两种具有EGFR失活突变（wa2和velvet）的不同小鼠模型中，人绒毛膜促性腺激素（hCG）诱导的Cyp19a1表达下调受损但未完全消除。在这两种小鼠模型中，hCG诱导的卵巢细胞外调节蛋白激酶1/2（ERK1/2）磷酸化、C/EBPβ表达以及连接蛋白43（ERK1/2作用的两个下游靶点）的磷酸化也降低。相反，EGFR信号传导的中断对hCG诱导的环磷腺苷酸反应元件结合蛋白（CREB）或蛋白激酶B（AKT）的磷酸化没有任何影响。这项研究提供了首个体内证据，将LH受体、EGFR和ERK1/2作为调节卵巢Cyp19a1表达的通路的连续组成部分联系起来。（《分子内分泌学》24卷：552 - 560页，2010年）
Ovarian follicular development and differentiation is characterized by dramatic changes in aromatase (Cyp19a1) expression. In preovulatory follicles, activation of the FSH receptor increases aromatase expression until the surge of LH decreases it. Here we provide in vivo evidence that down-regulation of Cyp19a1 by the LH surge requires efficient signaling through the epidermal growth factor receptor (EGFR). The human chorionic gonadotropin (hCG)-induced down-regulation of Cyp19a1 expression in the two different mouse models with inactivating mutations of the EGFR (wa2 and velvet) is impaired but not abolished. The hCG-induced phosphorylation of ovarian ERK1/2, expression of C/EBP beta, and the phosphorylation of Connexin43 (two downstream targets of ERK1/2 action) are also decreased in these two mouse models. In contrast, disruption of EGFR signaling does not have any affect on the hCG-induced phosphorylation of cAMP response element-binding protein or AKT. This study provides the first in vivo evidence linking the LH receptor, the EGFR, and ERK1/2 as sequential components of a pathway that regulates ovarian Cyp19a1 expression. (Molecular Endocrinology 24: 552-560, 2010)