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Submitted on December 10, 2003
Accepted on January 23, 2004
T2
Department of Reproductive Medicine (K.A.N., S.J.S., M.K.K., A.L.D., R.R., M.A.L.); The Center for the Study of Reproductive Biology and Disease (M.A.L.); Biomedical Sciences Graduate Program (K.A.N, A.L.D.); University of California, San Diego, La Jolla, California 92093-0674
* To whom correspondence should be addressed. E-mail: mlawson{at}ucsd.edu.
The hypothalamic neuropeptide hormone Gonadotropin-Releasing Hormone (GnRH) is the central regulator of reproductive function. GnRH stimulates the synthesis and release of the gonadotropins, Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), by the gonadotropes of the anterior pituitary through activation of the G-protein coupled GnRH receptor. In this study, we investigated the role of translational control of hormone synthesis by the GnRH receptor in the novel gonadotrope cell line L
T2. Using immunohistochemical and RIA studies with this model, we show that acute GnRH-induced synthesis and secretion of LH is dependent upon new protein synthesis but not new mRNA synthesis. We examined the response to GnRH and find that activation of cap-dependent translation occurs within 4 h. LH promoter activity was also examined and we find no increases in LH promoter activity after 6 h of GnRH stimulation. Additionally, we show that increased phosphorylation of translation initiation proteins, 4E-BP1, eIF4E and eIF4G, occur in a dose and time dependent manner in response to GnRH stimulation. Quantitative luminescent image analysis of Western blots shows that 10 nM GnRH is sufficient to cause a maximal increase in factor phosphorylation and maximal responses occur within 30 min of stimulation. Further, we demonstrate that the MAP kinase kinase (MEK) inhibitor, PD 98059 abolishes the GnRH-mediated stimulation of a cap dependent translation reporter. More specifically, we demonstrate that PD 98059 abolishes the GnRH-mediated stimulation of a downstream target of the extracellular signal regulated kinase (ERK) pathway, MAP kinase interacting kinase (Mnk1). Based on these findings, we conclude that acute GnRH stimulation of LT2 cells increases translation initiation through ERK signaling. This may contribute to the acute increases in LH subunit production.
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