Journal Title
Title of Journal: Endocrine
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Authors: Zhaochen Ning Xiaoling Du Ju Zhang Kuo Yang Lin Miao Yan Zhu Hui Yuan Linlin Wang Helmut Klocker Jiandang Shi
Publish Date: 2014/04/24
Volume: 47, Issue: 3, Pages: 901-912
Abstract
The regulation of the transcriptional activity of the estrogen receptorrelated receptor a ERRa has not yet been clearly documented Aromatase is a direct target gene of ERRa and we previously reported that prostaglandin E2 PGE2 increased the expression of ERRa in the prostate stromal cell line WPMY1 which ultimately promoted estradiol production by enhancing aromatase gene transcription Here we show that PGE2 also affects aromatase expression by regulating ERRa transcriptional activity in prostate stromal cells When the cells were cultured in serumfree medium the expression of aromatase was not proportional to the ERRa protein level if no other stimulation occurred indicating the absence of a factor that activates ERRa PGE2 could upregulate aromatase and ERRa response element ERREreporter expression and also enhance ERRa phosphorylation and nuclear localization PGE2 functions through the PGE2 receptors EP 2 and EP4 which couple to adenylate cyclase The activation of adenylate cyclase with Forskolin mimicked the PGE2mediated enhancement of extracellular signalregulated kinase ERK phosphorylation and ERRa target gene expression Experiments using specific signaling pathway inhibitors showed that both phosphatidylinositol 3kinase PI3K and ERK are involved in ERRa activation and the PI3K inhibitor was shown to abolish ERK activation Our results suggest that PGE2 is a modulator of ERRa transcriptional activity Furthermore PGE2 activates the EP2/EP4cAMPPI3KERK signaling pathway which enhanced ERRa transcriptional potentiality by increasing ERRa phosphorylation and nuclear translocation subsequently promoting the expression of its target genes such as aromataseWe thank Prof Vanacker Université de Lyon France for the gift of ERRa expression plasmid and ERRE luciferase reporter plasmid This research was funded by National Natural Science Foundation of China No 81370859 National Basic Research Programs 973 Programs No 2010CB945003 State Key Development Program for Basic Research of China 973 program No 2012CB723500 Tianjin Municipal Science and Technology Commission No 12ZCDZSY17000 the 111 Project No B08011
Keywords:
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