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This version published online on November 7, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0223
A more recent version of this article appeared on January 1, 2003
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Submitted on July 1, 2002
Accepted on October 17, 2002

A Central Role for Ets-2 in the Transcriptional Regulation and Cyclic AMP -Responsiveness of the Human Chorionic Gonadotropin-Beta Subunit Gene

Debjani Ghosh1, Toshihiko Ezashi1, Michael C. Ostrowski1, and R. Michael Roberts1*

1 Department of Animal Sciences, University of Missouri, Columbia, MO-65211, Department of Molecular Genetics, Ohio State University, Columbus, OH 43210

* To whom correspondence should be addressed. E-mail: RobertsRM{at}missouri.edu,.

Ets-2 has an important role in controlling the differentiation of the placenta. Here we show by truncation and mutational analysis that two closely spaced Ets-2 binding sites in the proximal promoter of the human chorionic gonadotropin {beta}5 (hCG{beta}5) gene constitute a major enhancer for hCG{beta} gene expression in JAr and JEG-3 human choriocarcinoma cells and in mouse NIH3T3 cells. Contrary to a previous report, we also demonstrate that the ability of Ets-2 to enhance transcription is subject to control by the Ras/Mitogen activated Protein kinase (MAPK) pathway, although this relationship is less easily demonstrable in JAr and JEG-3 choriocarcinoma cells than in the 3T3 cells, since the former already possess a fully activated MAPK pathway and contain Ets-2 phosphorylated at threonine residue at T72. Co-expression of Ets-2 and activated Ras in 3T3 cells led to activation of MEK-1/2, phosphorylation of Ets-2 at T72, and a ~120-fold up-regulation of reporter gene expression from a short (-175) hCG{beta} promoter. Fold activation in JAr and JEG-3 cells was rather less (20- to 30- fold), but basal activity was much higher. These effects on promoter activity were largely reversed in presence of the MAPK inhibitor PD98059, which prevents ERK1/2 activation, and partially reversed by mutating T72 on Ets-2. We finally show that the ability of 8-bromoadenosine 3/, 5/ cyclic monophosphate (8-Br-cAMP) to stimulate hCG{beta} promoter activity in JAr and JEG-3 cells occurs with a short promoter lacking the upstream elements previously considered to be essential for cAMP activation of the gene, and, through mutational analysis confirm that the major cAMP effects on the hCG{beta} promoter are mediated through the proximal Ets-2 enhancer. The data are consistent with the hypothesis that Ets-2 has a general and possibly essential role in controlling the activity of genes associated with trophectoderm differentiation.
Key words: Choriocarcinoma cell • 3T3 cell • cyclic AMP • MAP kinase • MEK1/2 • Ras • transcription factor • trophoblast




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