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Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
Address all correspondence and requests for reprints to: Dr. Mark S. Roberson, Department of Biomedical Sciences, T6–008a Veterinary Research Tower, Cornell University, Ithaca, New York 14853. E-mail: msr14{at}cornell.edu
Previous studies have shown that interaction of GnRH with its
serpentine, G protein-coupled receptor results in activation of the
extracellular signal regulated protein kinase (ERK) and the Jun
N-terminal protein kinase (JNK) pathways in pituitary gonadotropes. In
the present study, we examined GnRH-stimulated activation of an
additional member of the mitogen-activated protein kinase (MAPK)
superfamily, p38 MAPK. GnRH treatment of 
T3–1 cells resulted in
tyrosine phosphorylation of several intracellular proteins. Separation
of phosphorylated proteins by ion exchange chromatography suggested
that GnRH receptor stimulation can activate the p38 MAPK pathway.
Immunoprecipitation studies using a phospho-tyrosine antibody resulted
in increased amounts of immunoprecipitable p38 MAPK from T3–1 cells
treated with GnRH. Immunoblot analysis of whole cell lysates using a
phospho-specific antibody directed against dual phosphorylated p38
kinase revealed that GnRH-induced phosphorylation of p38 kinase was
dose and time dependent and was correlated with increased p38 kinase
activity in vitro. Activation of p38 kinase was blocked
by chronic phorbol ester treatment, which depletes protein kinase C
isozymes and 
. Overexpression of p38 MAPK and an activated form
of MAPK kinase 6 resulted in activation of c-jun and
c-fos reporter genes, but did not alter the expression
of the glycoprotein hormone -subunit reporter. Inhibition of p38
activity with SB203580 resulted in attenuation of GnRH-induced
c-fos reporter gene expression, but was not sufficient
to reduce GnRH-induced c-jun or glycoprotein hormone
-subunit promoter activity. These studies provide evidence that the
GnRH signaling pathway in T3–1 cells includes protein kinase
C-dependent activation of the p38 MAPK pathway. GnRH integration of
c-fos promoter activity may include regulation by p38
MAPK.
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