Modulation of GnRH-Stimulated LHβ Transcription by Steroid Hormones and the Ubiquitin-Proteasome System

Pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) regulates synthesis and release of the pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Transcription of the gonadotropin hormone subunit genes (α, LHβ and FSHβ) also depends on the frequency of GnRH pulses, but mechanisms underlying this specificity remain unknown. Furthermore, GnRH-stimulated gonadotropin subunit gene transcription can be modulated by steroid and peptide hormones to ensure the proper patterns of gonadotropin production needed for fertility. To elucidate mechanisms underlying GnRH-stimulated transcription, transcription factor associations with the LHβ promoter were measured using chromatin immunoprecipitation. LHβ expression requires Egr-1 and SF-1; with GnRH, Egrand 1 SF-1 associations were stimulated, cyclic, and coincidental, with a period of approximately 30 minutes. Proteasome inhibition prevented rhythmic LHβ promoter occupancy during GnRH and inhibited stimulation of LHβ transcription. Egr-1, but not SF-1, protein synthesis was induced by GnRH and Egr-1 accumulated when the proteasome was blocked. Ubiquitinated forms of Egr-1 and SF-1 associated with the LHβ promoter, suggesting their degradation may be crucial for LHβ proteasome-dependent transcription. These results demonstrate that degradation via the proteasome is vital to GnRH-stimulated LHβ expression and proper transcription factor associations with the LHβ promoter. Modulation of GnRH signals within the pituitary alters the expression of ii the gonadotropin subunit genes. FSHβ transcription was enhanced by androgens in an ERK1/2-dependent manner involving downregulation of the phosphatase, MKP1. GnRH-stimulated LHβ transcription relied on JNK but not ERK1/2, indicating that MAPK pathways can selectively signal to LHβ or FSHβ. The differential regulation of LH and FSH by pulsatile GnRH is central to the female reproductive cycle, where large fluctuations in gonadotropins occur. Estradiol (E) can exert positive feedback on gonadotropes prior to the preovulatory LH surge. E enhanced GnRH stimulation of LHβ and α-subunit reporter genes, and upregulated levels of a transcriptional activator (Egr-1) while decreasing levels of a transcriptional repressor (Zfhx1). cAMP signaling also enhanced GnRH-stimulated LHβ transcription. Thus, the GnRH signaling to the gonadotropin subunit genes involves signaling pathway specificity and the ubiquitin-proteasome system. The gonadotrope response to GnRH can be modified by steroid/peptide hormones, which act on multiple components of GnRH-stimulated signaling pathways.

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