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Extracellular Signal-Regulated Kinase, Jun N-Terminal Kinase, p38, and c-Src Are Involved in Gonadotropin-Releasing Hormone-Stimulated Activity of the Glycoprotein Hormone Follicle-Stimulating Hormone ß-Subunit Promoter

Departments of Biochemistry (D.B., D.C., Z.N.) and Cell Research and Immunology (D.S., I.F.), The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel; Department of Biological Regulation (S.K., R.S.), The Weizmann Institute of Science, Rehovot 76100, Israel; and Human Reproduction Sciences Unit, Medical Research Council (Z.N.), The University of Edinburgh, Edinburgh EH164SB, United Kingdom

Address all correspondence and requests for reprints to: Dr. Zvi Naor, Human Reproduction Sciences Unit, Medical Research Council, The University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH164SB, United Kingdom. E-mail: z.naor{at}hrsu.mrc.ac.uk.

The role of ERK, Jun N-terminal kinase (JNK), p38, and c-Src in GnRH-stimulated FSHß-subunit promoter activity was examined in the LßT-2 gonadotroph cell line. Incubation of the cells with a GnRH agonist resulted in activation of ERK, JNK, p38, and c-Src. The peak of ERK activation was observed at 5 min, whereas that of JNK, p38, and c-Src at 30 min, declining thereafter. ERK activation by GnRH is dependent on protein kinase C (PKC), as evident by activation, inhibition, and depletion of 12-O-tetradecanoylphorbol-13-acetate-sensitive PKC subspecies. Ca²⁺ influx, but not Ca²⁺ mobilization, is required for ERK activation. GnRH signaling to ERK is partially mediated by dynamin and a protein tyrosine kinase, apparently c-Src. ERK activation by GnRH in LßT-2 cells does not involve transactivation of epidermal growth factor receptor or mediation via Gß or ß-arrestin. Once activated by GnRH, ERK translocates to the nucleus. We examined the role of ERK, JNK, p38, and c-Src in GnRH-stimulated ovine FSHß promoter, linked to a luciferase reporter gene (–4741oFSHß-LUC). The PKC activator 12-O-tetradecanoylphorbol-13-acetate, but not the Ca²⁺ ionophore ionomycin, stimulated FSHß-luciferase (LUC) activity. Furthermore, down-regulation of PKC, but not removal of Ca²⁺, inhibited the GnRH response. Cotransfection of FSHß-LUC and the constitutively active forms of Raf-1 and MEK stimulated FSHß-LUC activity, whereas the dominant negatives of Ras, Raf-1, and MEK and the selective MEK inhibitor PD98059, abolished GnRH-induced FSHß-LUC activity. The dominant negatives of CDC42 and JNK reduced the GnRH response by 36 and 49%, respectively. Incubation of the cells with the p38 or the c-Src inhibitors SB203580 and PP1 also reduced the GnRH response. Surprisingly, two proximal activator protein-1 sites contribute very little to the GnRH response. Thus, PKC, ERK, JNK, p38, and c-Src, but not Ca²⁺, are involved in GnRH induction of the ovine FSHß gene.

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