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Endocrinology Vol. 143, No. 5 1651-1659
Copyright © 2002 by The Endocrine Society

INTRACELLULAR SIGNAL SYSTEMS

Transcriptional Activation of the Ovine Follicle-Stimulating Hormone-ß Gene by Gonadotropin- Releasing Hormone Involves Multiple Signal Transduction Pathways

Vyacheslav V. Vasilyev, Flavia Pernasetti, Suzanne B. Rosenberg, Mark J. Barsoum, Darrell A. Austin, Nicholas J. G. Webster and Pamela L. Mellon

Departments of Reproductive Medicine (F.P., V.V.V., S.B.R., M.J.B., P.L.M.), Neuroscience (V.V.V., P.L.M.), and Medicine (N.J.G.W.), University of California-San Diego, La Jolla, California 92093-0674; and Medical Research Service (N.J.G.W., D.A.A.), San Diego Veterans Affairs Healthcare System, San Diego, California 92161

Address all correspondence and requests for reprints to: Pamela L. Mellon, Ph.D., Department of Reproductive Medicine 0674, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: . pmellon{at}ucsd.edu

GnRH regulates gonadotrope cells through GnRH receptor activation of the PKC-, MAPK-, and calcium-activated signaling cascades. Due to the paucity of homologous model systems expressing FSHß, little is known about the specific mechanisms involved in transcriptional regulation of this gene by GnRH. Previous studies from our laboratory demonstrated that the gonadotrope-derived LßT2 cell line expresses FSHß mRNA. In the present study we characterized the mechanisms involved in GnRH regulation of the FSHß promoter using this cell model. Using transfection assays, we show that GnRH regulation of the ovine FSHß promoter involves at least two elements, present between -4152/-2878 and -2550/-1089 bp, in association with one or several elements within the proximal region of the promoter. Surprisingly, the two activating protein-1 sites previously shown to be involved in the FSHß response to GnRH in heterologous cells do not play a role in GnRH responsiveness in the gonadotrope cell model. Here we demonstrate that calcium influx itself is not sufficient to confer the response, but it is necessary for both 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and GnRH induction of the FSHß gene. Moreover, we show that GnRH regulation of FSHß gene expression is mediated by PKC and establish the presence of multiple PKC isozymes in LßT2 cells. Interestingly, GnRH and TPA induce activity of the FSHß promoter through different, although possibly overlapping, pools of PKC isoforms. This is further supported by the use of a MAPK inhibitor, which abolishes the induction of FSHß by GnRH, but not by TPA. In conclusion, we have demonstrated that calcium, PKC, and MAPK signaling systems are all involved in the induction of FSHß gene expression by GnRH in the LßT2 mouse gonadotrope cell model.




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