Activator Protein-1 and Smad Proteins Synergistically Regulate Human Follicle-Stimulating Hormone β-Promoter Activity

• DOI: 10.1210/en.2008-0220
• Publication Date: 2008-07-25T01:10:28Z
• Authors: Ying Wang; Jérôme Fortin; Pankaj Lamba; Marco Bonomi; Luca Persani; Mark S. Roberson; Daniel J. Bernard
• Keywords: JUNB; FOSB; AP-1 transcription factor

GnRH1 stimulates the synthesis and secretion of FSH LH from anterior pituitary gland. The molecular mechanisms through which produces these effects in humans have not been determined. Here, we examined transcriptional regulation human FSHβ (FSHB) subunit using reporter assays immortalized murine gonadotrope cells. dose time dependently stimulated FSHB promoter activity, with peak stimulation occurring at 8 h. rapidly various MAPK cascades, though ERK1/2 p38 pathways appeared to be most critical for induction. Indeed, constitutively active forms both Raf1 kinase MAP2K6 (MKK6) were sufficient stimulate activity. activator protein-1 (AP-1) (FosB, c-fos, JunB, cJun) complex formation, latter bound a conserved cis-element within −120 bp transcription start site. A second, lower affinity, site was mapped more proximally. Mutations cis-elements diminished GnRH1-stimulated disruption higher affinity had dramatic effect. dominant-negative Fos protein inhibited transcription, confirming role endogenous AP-1 proteins. 1 (MEK1) inhibitors significantly attenuated FosB, JunB synthesis, suggesting mechanism whereby signaling regulate transcription. Activins inhibins potently rodents, but their roles are less clear. Activin A, weak on its own, synergized In contrast, activin partially LHβ (LHB) appear converge level high-affinity Jun proteins synergistically activity this element, potentiated by coexpression either Smad2 or Smad3, effectors cascade. summary, combined actions Smad acting element provide candidate ability activins potentiate selectively expression suggests model preferential increases luteal-follicular transition menstrual cycle.