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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, California 92093
Address all correspondence and requests for reprints to: Pamela L. Mellon, Ph.D., Department of Reproductive Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: pmellon{at}ucsd.edu.
FSH is produced by the pituitary gonadotrope to regulate gametogenesis. Production of the ß-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 ß-subunit gene. Although both activin and glucocorticoids are notable regulators of FSHß by themselves, we find that cotreatment results in a synergistic interaction on the mouse FSHß promoter at the level of the gonadotrope using transient transfection of a reporter gene into the LßT2 immortalized gonadotrope-derived cell line. This synergistic interaction is specific to FSHß, because only additive effects of these two hormones are observed on LH ß-subunit, GnRH receptor, and mouse mammary tumor virus 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 FSHß promoter that contribute to the synergistic response as well. We also identify novel activin-responsive regions in the mouse FSHß promoter and find that the –120 site can bind Smad2/3 in vitro. In addition, the glucocorticoid receptor and Smad3 are sufficient to confer a striking synergy with glucocorticoids on the mouse FSHß 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 FSHß promoter.
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P. Lamba, V. Khivansara, A. C. D'Alessio, M. M. Santos, and D. J. Bernard Paired-Like Homeodomain Transcription Factors 1 and 2 Regulate Follicle-Stimulating Hormone {beta}-Subunit Transcription through a Conserved cis-Element Endocrinology, June 1, 2008; 149(6): 3095 - 3108. [Abstract] [Full Text] [PDF]
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V. G. Thackray and P. L. Mellon Synergistic Induction of Follicle-Stimulating Hormone {beta}-Subunit Gene Expression by Gonadal Steroid Hormone Receptors and Smad Proteins Endocrinology, March 1, 2008; 149(3): 1091 - 1102. [Abstract] [Full Text] [PDF]
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K. M. Breen, T. L. Davis, L. C. Doro, T. M. Nett, A. E. Oakley, V. Padmanabhan, L. A. Rispoli, E. R. Wagenmaker, and F. J. Karsch Insight into the Neuroendocrine Site and Cellular Mechanism by which Cortisol Suppresses Pituitary Responsiveness to Gonadotropin-Releasing Hormone Endocrinology, February 1, 2008; 149(2): 767 - 773. [Abstract] [Full Text] [PDF]
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