Estrogen- and xenoestrogen-induced ERK signaling in pituitary tumor cells involves estrogen receptor-伪 interactions with G protein-伪i and caveolin I

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• 作者：Cheryl S. Watson ; ^{cswatson@utmb.edu} ; Yow-Jiun Jeng ^{yjeng@utmb.edu} ; Guangzhen Hu ^{Hu.Guangzhen@mayo.edu} ; Ann Wozniak ^{awozniak@kumc.edu} ; Nataliya Bulayeva ^{Nataliya.Bulayeva@uth.tmc.edu} ; Jutatip Guptarak ^{juguptat@utmb.edu}
• 关键词：AP ; alkylphenol ; Ab ; antibody ; BPA ; bisphenol A ; GPR30 or GPER ; G protein-coupled estrogen receptor ; E1 ; estrone ; E2 ; estradiol ; E3 ; estriol ; ERK ; extracellular-regulated kinase ; mER伪 ; membrane estrogen receptor-伪 ; mER尾 ; membrane estrogen receptor-尾
• 刊名：Steroids
• 出版年：2012
• 期刊代码：142_0039128x
• 类别：bio
• 出版时间：April, 2012
• 卷：77
• 期：5
• 页码：424-432
• 文件大小：650 K

摘要

Multiple physiologic estrogens (estradiol, estriol, and estrone), as well as xenoestrogenic compounds (including alkylphenols and bisphenol A), can act via nongenomic signaling initiated by liganding of the plasma membrane estrogen receptor-伪 (mER伪). We examined heterotrimeric G protein involvement leading to extracellular-regulated kinase (ERK) activation in GH3/B6/F10 rat anterior pituitary tumor cells that express abundant mER伪, and smaller amounts of mER尾 and GPR30. A combination of microarrays, immunoblots, and quantitative immunoassays demonstrated the expression of members of all 伪, 尾, and 纬 G protein classes in these cells. Use of selective inhibitors showed that the G_伪i subtype was the primary initiator of downstream ERK signaling. Using antibodies against the GTP-bound form of G_伪 protein subtypes i and s, we showed that xenoestrogens (bisphenol A, nonylphenol) activated G_伪i at 15-30 s; all alkylphenols examined subsequently suppressed activation by 5 min. GTP-activation of G_伪i for all estrogens was enhanced by irreversible cumulative binding to GTP纬S. In contrast, G_伪s was neither activated nor deactivated by these treatments with estrogens. ER伪 and G_伪i co-localized outside nuclei and could be immuno-captured together. Interactions of ER伪 with G_伪i and caveolin I were demonstrated by epitope proximity ligation assays. An ER伪/尾 antagonist (ICI182780) and a selective disruptor of caveolar structures (nystatin) blocked estrogen-induced ERK activation. m>Conclusions:m> Xenoestrogens, like physiologic estrogens, can evoke downstream kinase signaling involving selective interactions of ER伪 with G_伪i and caveolin I, but with some different characteristics, which could explain their disruptive actions.