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Upregulation of Egr-1 biosynthesis in pituitary gonadotropes following activation of GnRH and muscarinic acetylcholine receptors

Stimulation of pituitary gonadotropes expressing the Gq/11-coupled gonadotropin releasing hormone (GnRH) and muscarinic M3 acetylcholine receptors with GnRH or carbachol upregulates the biosynthesis of the zinc finger transcription factor Egr-1. Receptor stimulation activates phospholipase C, leading to elevated cytosolic Ca2+ levels following stimulation. Accordingly, GnRH- and carbachol-triggered biosynthesis of Egr-1 was blocked by BAPTA-AM, an intracellular calcium chelator. Ca2+-mediated activation of extracellular signal-regulated protein kinase (ERK) was accomplished via activation of protein kinase C and transactivation of the EGF receptor. Calmodulin was also required to connect GnRH and carbachol signaling with the upregulation of Egr-1 gene transcription. Lentiviral-mediated expression of a dominant-negative mutant of Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, impaired GnRH- and carbachol-induced biosynthesis of Egr-1. Thus, Elk-1 connects the GnRH- and carbachol-induced signaling cascades in the nucleus with the Egr-1 gene. Lentiviral-mediated expression of MAP kinase phosphatase-1 (MKP-1), the enzyme that dephosphorylates and inactivates ERK, completely blocked Egr-1 biosynthesis following GnRH or carbachol stimulation, indicating that MKP-1 functions as a nuclear shut-of-device of these signaling pathways. Chromatin immunoprecipitation experiments revealed that Egr-1 bound in vivo to the regulatory regions of the basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGFbeta) genes following stimulation of the cells with GnRH or carbachol. As a result, elevated levels of bFGF and TGFbeta mRNA were detected in GnRH and carbachol stimulated gonadotropes, corroborating the view that Egr-1 transactivates the bFGF and TGFbeta genes following stimulation of the cells with GnRH or carbachol.

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Correspondence to Sabine I Mayer.

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  • Acetylcholine Receptor
  • Carbachol
  • Muscarinic Acetylcholine
  • Muscarinic Acetylcholine Receptor
  • Zinc Finger Transcription Factor