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Molecular Endocrinology 16 (3): 419-434
Copyright © 2002 by The Endocrine Society

GnRH Activates ERK1/2 Leading to the Induction of c-fos and LHß Protein Expression in LßT2 Cells

Fujun Liu, Darrell A. Austin, Pamela L. Mellon, Jerrold M. Olefsky and Nicholas J. G. Webster

Departments of Medicine (F.L., J.M.O., N.J.G.W.) and Reproductive Medicine (P.L.M.) and the University of California San Diego Cancer Center (P.L.M., N.J.G.W.), University of California, San Diego, California 92093; and the Medical Research Service (D.A.A., N.J.G.W.), San Diego Veterans Healthcare System, San Diego, California 92161

Address all correspondence and requests for reprints to: Nicholas Webster, Department of Medicine 0673, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673. E-mail: nwebster{at}ucsd.edu.

GnRH acts on pituitary gonadotropes to stimulate the synthesis and release of LH and FSH. However, the signaling pathways downstream of the GnRH receptor that mediate these effects are not fully understood. In this paper, we demonstrate that GnRH activates ERK, c-Jun N-terminal kinase, and p38MAPK in the LßT2 gonadotrope cell line. Phosphorylation of both ERK and p38MAPK are stimulated rapidly, 30- to 50-fold in 5 min, but activation of c-Jun N-terminal kinase has slower kinetics, reaching only 10-fold after 30 min. Activation of ERK by GnRH is blocked by inhibition of MAPK kinase (MEK) and partially blocked by inhibition of PKC and calcium, but not PI3K or p38MAPK signaling. We demonstrate that phosphorylated ERK accumulates in the nucleus in a PKC-dependent manner. We also show that GnRH induces c-fos and LHß subunit protein expression in LßT2 cells via MEK. Experiments with EGTA or calcium channel antagonists indicated that calcium influx is important for the induction of both genes by GnRH. In conclusion, these results show that GnRH activates all three MAPK subfamilies in LßT2 cells and induces c-fos and LHß protein expression through calcium and MEK-dependent mechanisms. These results also demonstrate that the nuclear translocation of ERK by GnRH requires PKC signaling.




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