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Submitted on July 17, 2006
Accepted on October 23, 2006
-Subunit Gene Expression in the Immortalized LT2 Gonadotrope Cell Line
Departments of Reproductive Medicine and Neurosciences, the Biomedical Sciences Graduate Program, and the Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093-0674
* To whom correspondence should be addressed. E-mail: pmellon{at}ucsd.edu.
Follicle-stimulating hormone (FSH) is produced by the pituitary gonadotrope to regulate gametogenesis. Production of the 
subunit of FSH is the rate-limiting step in FSH synthesis and a number of peptide and steroid hormones within the reproductive axis have been found to regulate transcription of the FSH -subunit gene. Although both activin and glucocorticoids are notable regulators of FSH by themselves, we find that co-treatment results in a synergistic interaction on the mouse FSH promoter at the level of the gonadotrope using transient transfection of a reporter gene into the LT2 immortalized gonadotrope-derived cell line. This synergistic interaction is specific to FSH, as only additive effects of these two hormones are observed on luteinizing hormone (LH) -subunit, gonadotropin-releasing hormone receptor (GnRHR), and mouse mammary tumor virus (MMTV) gene expression. Components of both activin and glucocorticoid signaling are found to be necessary for synergy and there are specific cis elements on the mouse FSH promoter that contribute to the synergistic response as well. We also identify novel activin responsive regions in the mouse FSH promoter and find that the -120 site can bind Smad2/3 in vitro. In addition, the glucocorticoid receptor (GR) and Smad3 are sufficient to confer a striking synergy with glucocorticoids on the mouse FSH promoter. Our studies provide the first evidence of a synergistic interaction between activin and glucocorticoids within the gonadotrope cell and demonstrate that this synergy can occur directly at the level of the mouse FSH promoter.
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