Nelson-Degrave Velen L, Wickenheisser Jessica K, Hendricks Karen L, Asano Tomoichiro, Fujishiro Midori, Legro Richard S, Kimball Scot R, Strauss Jerome F, McAllister Jan M
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine 500 University Drive H166, Hershey, Pennsylvania 17033, USA.
Mol Endocrinol. 2005 Feb;19(2):379-90. doi: 10.1210/me.2004-0178. Epub 2004 Oct 28.
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.
我们研究了丝裂原活化蛋白激酶（MAPK）信号通路在多囊卵巢综合征（PCOS）女性雄激素生物合成增加及CYP17基因表达中的作用。对传代培养的正常和PCOS卵泡膜细胞中MAPK激酶（MEK1/2）和细胞外信号调节激酶1/2（ERK1/2）磷酸化水平的比较显示，与正常细胞相比，PCOS细胞中MEK1/2磷酸化水平降低超过70%，ERK1/2磷酸化水平降低50%。用显性负性MEK1感染可增加CYP17 mRNA和脱氢表雄酮（DHEA）丰度，而持续激活的MEK1则降低DHEA生成及CYP17 mRNA丰度。同样，MEK抑制剂PD98059可使CYP17 mRNA积累及CYP17启动子活性增加至PCOS细胞中的水平。值得注意的是，在完全缺乏胰岛素的条件下培养的卵泡膜细胞中，与正常卵泡膜细胞相比，PCOS卵泡膜细胞中ERK1/2磷酸化水平降低，而PCOS卵泡膜细胞中CYP17 mRNA及DHEA合成增加。这些研究表明，在PCOS细胞中，无论胰岛素浓度如何，活化的MEK1/2和ERK1/2水平降低均与雄激素生成增加相关。这些发现提示MAPK通路改变参与了PCOS患者卵巢雄激素过度生成的发病机制。
