Differential activation of the luteinizing hormone beta-subunit promoter by activin and gonadotropin-releasing hormone: a role for the mitogen-activated protein kinase signaling pathway in LbetaT2 gonadotrophs.
LH consists of alpha- and beta-subunits, and synthesis of the beta-subunit has been reported to be the rate-limiting step in LH production. In this study, we found that activin A increased both the LHbeta mRNA level and LH content in cells of the gonadotroph cell line, LbetaT2. We next examined the effects of activin A and GnRH on LHbeta promoter activity by reporter gene assay and compared the signal transduction pathways. Activin A and GnRH activated the LHbeta 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 LHbeta 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 LbetaT2 cells. Overexpression of constitutively active MEK1 or MEK kinase activated both MAP kinase and the LHbeta 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 LHbeta promoter via the MAP kinase pathway and that activin A-induced activation of the LHbeta promoter is independent of the MAP kinase pathway.
D028341:Activins / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology* / Q000502:physiology; D028322:Inhibin-beta Subunits / Q000494:pharmacology* / Q000502:physiology; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics* / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D027602:Serum Response Element / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D002070:Butadienes; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D005419:Flavonoids; D037101:Luteinizing Hormone, beta Subunit; D009570:Nitriles; D012333:RNA, Messenger; C113580:U 0126; C422405:activin A; D028341:Activins; D007987:Gonadotropin-Releasing Hormone; D028322:Inhibin-beta Subunits; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482578:Map3k1 protein, mouse; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D009543:Nifedipine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one