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Activation of MAPK Cascades by GnRH: ERK and Jun N-Terminal Kinase Are Involved in Basal and GnRH-Stimulated Activity of the Glycoprotein Hormone LHß-Subunit Promoter

Department of Biochemistry (D.H., D.B., D.C., Z.N.), The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel; and Department of Biological Regulation (S.K., R.S.), The Weizmann Institute of Science, Rehovot 76100, Israel

Address all correspondence and requests for reprints to: Dr. Zvi Naor, Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: . Naorzvi{at}post.tau.ac.il

The role of ERK and Jun N-terminal kinase (JNK) in basal- and GnRH-stimulated LHß-promoter activity was examined in the gonadotroph cell line LßT-2. GnRH agonist (GnRH-A) stimulates the MAPK cascades ERK, JNK, and p38MAPK, with a peak at 7 min for ERK and at 60 min for JNK and p38MAPK. The rat glycoprotein hormone LHß-subunit promoter, linked to the chloramphenicol acetyl transferase (CAT) reporter gene, was used to follow its activation. Addition of GnRH-A (10 nM) to LßT-2 cells resulted in a 6-fold increase in LHß-CAT activity at 8 h, which was markedly reduced by a GnRH antagonist. The PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA), but not the Ca²⁺ ionophore ionomycin, stimulated LHß-CAT activity. Addition of GnRH-A and TPA together did not produce an additive response. Down-regulation of PKC, but not removal of Ca²⁺, abolished the GnRH-A and the TPA response. Cotransfection of the LHß-promoter and the constitutively active form of Raf-1 stimulated basal and GnRH-A-induced LHß-CAT activity. The dominant negative forms of the ERK cascade members Ras, Raf-1, and MAPK/ERK kinase (MEK) markedly reduced basal and GnRH-A-induced LHß-CAT activity, Similar results were obtained with the MEK inhibitor PD 098059. Cotransfection of the LHß-promoter and the constitutively active CDC42 stimulated basal and GnRH-A-induced LHß-CAT activity. The dominant negative forms of the JNK cascade members Rac, CDC42, and SEK markedly diminished basal and GnRH-A-induced LHß-CAT activity. Interestingly, the constitutively active form of c-Src stimulated the basal and the GnRH-A response, whereas the dominant negative form of c-Src, or the c-Src inhibitor PP1 diminished basal and the GnRH-A response. We conclude that ERK and JNK are involved in basal and GnRH-A stimulation of LHß-CAT activity. c-Src participates also in LHß-promoter activation by a mechanism which might be linked to ERK and JNK activation.

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