Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome
Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome
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DOI：
10.1210/me.2004-0178
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发表时间：
2005-02-01
影响因子：
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通讯作者：
McAllister, JM
中科院分区：
文献类型：
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作者：
Nelson-Degrave, VL;Wickenheisser, JK;McAllister, JM
我们研究了MAPK信号通路在多囊卵巢综合征（PCOS）患者雄激素生物合成和CYP 17基因表达增加中的作用。比较增殖的正常和PCOS卵泡膜细胞中MAPK激酶（MEK 1/2）和ERK 1/2磷酸化，发现与正常细胞相比，PCOS细胞中MEK 1/2磷酸化降低超过70%，ERK 1/2磷酸化降低50%。显性阴性的MEK 1感染增加CYP 17 mRNA和脱氢表雄酮（DHEA）的丰度，而组成型活性的MEK 1减少DHEA生产和CYP 17 mRNA丰度。类似地，MEK抑制剂PD 98059将CYP 17 mRNA积累和CYP 17启动子活性增加至在PCOS细胞中观察到的水平。值得注意的是，在卵泡膜细胞保持在完全没有胰岛素，ERK 1/2磷酸化减少PCOS卵泡膜细胞相比，正常卵泡膜细胞，CYP 17 mRNA和DHEA合成增加PCOS卵泡膜细胞。这些研究表明，在多囊卵巢综合征细胞中，无论胰岛素浓度如何，活化的MEK 1/2和ERK 1/2水平的降低与雄激素产生的增加相关。这些发现暗示了MAPK通路的改变在PCOS患者卵巢雄激素过度产生的发病机制中的作用。
We have investigated the involvement of the MAPK signaling pathway in increased androgen biosynthesis and CYP17 gene expression in women with polycystic ovary syndrome ( PCOS). A comparison of MAPK kinase (MEK1/2) and ERK1/2 phosphorylation in propagated normal and PCOS theca cells, revealed that MEK1/2 phosphorylation was decreased more than 70%, and ERK1/2 phosphorylation was reduced 50% in PCOS cells as compared with normal cells. Infection with dominant-negative MEK1 increased CYP17 mRNA and dehydroepiandrosterone ( DHEA) abundance, whereas constitutively active MEK1 reduced DHEA production and CYP17 mRNA abundance. Similarly, the MEK inhibitor, PD98059, increased CYP17 mRNA accumulation and CYP17 promoter activity to levels observed in PCOS cells. Remarkably, in theca cells maintained in the complete absence of insulin, ERK1/2 phosphorylation was decreased in PCOS theca cells as compared with normal theca cells, and CYP17 mRNA and DHEA synthesis were increased in PCOS theca cells. These studies demonstrate that in PCOS cells reduced levels of activated MEK1/2 and ERK1/2 are correlated with increased androgen production, irrespective of the insulin concentration. These findings implicate alterations in the MAPK pathway in the pathogenesis of excessive ovarian androgen production in PCOS.