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Synergy between Activin A and Gonadotropin-Releasing Hormone in Transcriptional Activation of the Rat Follicle-Stimulating Hormone-ß Gene

Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Ursula B. Kaiser, Brigham and Women’s Hospital and Harvard Medical School, Division of Endocrinology, Diabetes and Hypertension, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: ukaiser{at}partners.org.

Both activin and GnRH can independently stimulate expression of the FSHß subunit gene. In this study, we used the gonadotrope-derived LßT2 cell line to investigate the potential interaction between activin and GnRH in regulating the transcriptional activity of the rat FSHß gene promoter. Activin A and GnRH synergistically enhanced rat FSHß transcriptional activity. Overexpression of SMAD3 (mediator of decapentaplegic-related protein 3), but not of SMAD2, increased transcriptional activation of the rat (r) FSHß gene promoter, which was further enhanced by the combined overexpression of SMAD3 and 4 (3+4). The stimulatory effects of SMAD3 overexpression were localized to –472/–256 of the rFSHß gene promoter, and activin- and GnRH-responsive proteins were shown to bind to region –284/–252. Sequence analysis identified a consensus palindromic SMAD-binding site at –266/–259 of the rFSHß gene promoter. Mutation of two bases located in the center of this palindrome effectively abrogated SMAD4 binding, markedly reduced SMAD3 and 3+4 stimulation of the rFSHß gene promoter, and significantly decreased the synergistic enhancement of promoter activity by both activin A and GnRH, and SMAD3 and GnRH. Blockade of the MAPK-signaling pathway did not significantly affect the response to combined stimulation with activin and GnRH. In contrast, interference with SMAD3 signaling caused a significant reduction in activin and GnRH synergy. The results indicate that SMAD3 plays an important role in the synergistic effects of activin and GnRH and demonstrate that this synergy is mediated by a palindromic cis-element located at –266/–259 of the rFSHß gene promoter.

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