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Differential Activation of the Luteinizing Hormone ß-Subunit Promoter by Activin and Gonadotropin-Releasing Hormone: A Role for the Mitogen-Activated Protein Kinase Signaling Pathway in LßT2 Gonadotrophs¹

Department of Molecular Pharmacology,³ Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan Department of Obstetrics and Gynecology,⁴ Shimane University School of Medicine, Izumo 693-8501, Japan

LH consists of - and ß-subunits, and synthesis of the ß-subunit has been reported to be the rate-limiting step in LH production. In this study, we found that activin A increased both the LHß mRNA level and LH content in cells of the gonadotroph cell line, LßT2. We next examined the effects of activin A and GnRH on LHß promoter activity by reporter gene assay and compared the signal transduction pathways. Activin A and GnRH activated the LHß promoter, and the response to a combination of activin A and GnRH was higher than that to activin A or GnRH alone. The effects of activin A and GnRH were specifically inhibited by inhibin-like peptide and antide, a GnRH antagonist, respectively. The activation of the LHß promoter by GnRH was inhibited by PD098059 and U0126, MAP kinase kinase (MEK) inhibitors. In contrast, these protein kinase inhibitors did not inhibit the activin A-induced activation. GnRH, but not activin A, activated MAP kinase in LßT2 cells. Overexpression of constitutively active MEK1 or MEK kinase activated both MAP kinase and the LHß promoter. Furthermore, GnRH, but not activin A, strongly induced SRE-mediated transcription, a known target of the MAP kinase pathway. These results suggest that GnRH activates the LHß promoter via the MAP kinase pathway and that activin A-induced activation of the LHß promoter is independent of the MAP kinase pathway.

¹ This work was supported in part by Grants-in-Aid for Scientific Research and for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan; by a research grant from the Human Frontier Science Program (H.Y. and E.M.); and by a grant from the Ministry of Health and Welfare (K.M.).

² Correspondence: Hideyuki Yamamoto, Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. FAX: 81 96 373 5078; hideyuki{at}gpo.kumamoto-u.ac.jp

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