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This version published online on January 6, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0320
A more recent version of this article appeared on April 1, 2005
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Submitted on August 9, 2004
Accepted on December 22, 2004

Coordinate regulation of basal and cAMP-activated expression of hCG{alpha} by Ets-2 and CREB

Debjani Ghosh, Shrikesh Sachdev, Mark Hannink, and R. Michael Roberts*

Departments of Animal Sciencesand Biochemistry, University of Missouri, Columbia, MO 65211

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

Ets-2 controls the activities of many genes characteristically up regulated in trophoblast. One apparent exception has been the gene for the human chorionic gonadotropin subunit alpha, hCG{alpha}. Here we show that the hCG{alpha} gene contains two overlapping Ets binding sites adjacent to an AP1-like site in its proximal promoter. Transactivation by Ets-2 is susceptible to truncation and mutation of these sites, which bind Ets-2 during in vitro mobility shift assays, as well as in vivo as determined by chromatin immunoprecipitation in choriocarcinoma cells. Knockdown of Ets-2 with siRNA decreases both promoter activity and synthesis of hCG{alpha}. Ets-2 acts in combination with the protein kinase A signal transduction pathway to activate the hCG{alpha} promoter expression. Mutation of the Ets-2 binding sites dramatically reduces up-regulation by protein kinase A, while mutations within the two CREs abolish responsiveness of the promoter to Ets-2. CREB and Ets-2 form a complex that can be co-immunoprecipitated from choriocarcinoma cells and association of CREB and Ets-2 is increased by activation of protein kinase A. Regulation of hCG{alpha} subunit gene activity by cAMP involves both the binding of CREB and Ets-2 to discrete elements in the promoter as well as a physical interaction between the two proteins. We propose that regulation of hCG{alpha} by Ets-2 and CREB enables coordinated expression of hCG{alpha} with its partner hCG{beta} subunit.
Key words: choriocarcinoma • CRE • CREB • Ets • human chorionic gonadotropin • MAP kinase • pregnancy • protein kinase A • transcriptional control • trophoblast • chromatin immunoprecipitation




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