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Submitted on October 22, 2003
Accepted on January 14, 2004
-Subunit Promoter
Departments of Biochemistry (D.B., D.C., Z.N.), 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; Human Reproduction Sciences Unit, Medical Research Council (Z.N.), The University of Edinburgh Chancellor's Building, 49 Little France Crescent, Edinburgh EH164SB
* To whom correspondence should be addressed. E-mail: z.naor{at}hrsu.mrc.ac.uk.
The role of ERK, JNK, p38 and c-Src in GnRH-stimulated FSH
-subunit promoter activity was examined in the LT-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 5min, while that of JNK, p38 and c-Src at 30min, declining thereafter. ERK activation by GnRH is dependent on protein kinase C (PKC), as evident by activation, inhibition and depletion of TPA-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 (PTK), apparently c-Src. ERK activation by GnRH in LT-2 cells does not involve transactivation of EGF receptor (EGFR), or mediation via G
or -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 FSH-promoter, linked to a luciferase reporter gene (-4741oFSH-LUC). The PKC activator TPA, but not the Ca2+ ionophore ionomycin, stimulated FSHLUC activity. Furthermore, down-regulation of PKC, but not removal of Ca2+, inhibited the GnRH response. Co-transfection of FSH-LUC and the constitutively active (CA) forms of Raf-1 and MEK stimulated FSH-LUC activity, while the dominant negatives (DN) of Ras, Raf-1 and MEK and the selective MEK inhibitor PD98059, abolished GnRH-induced FSH-LUC activity. The DN 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 AP-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 oFSH gene.
gene •
pituitary cells •
LT2 cells
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