Cold-Shock-Domain Protein A (CSDA) Contributes Posttranscriptionally to Gonadotropin-Releasing Hormone-Regulated Expression of Egr1 and Indirectly to Lhb1

Abstract

Gonadotropin-releasing hormone (GnRH), a hypothalamic neurohormone, regulates transcription of Lhb in gonadotrophs indirectly through transient induction and accumulation of EGR1, a zinc finger transcription factor. AlphaT3 and LbetaT2 cell lines model gonadotrophs at two distinct stages of development, prenatal and postnatal expression of Lhb. Although GnRH induces EGR1 in both cell lines, the levels of the DNA-binding protein are lower and disappear more quickly in alphaT3 than in LbetaT2 cells. Herein we show that overexpression of Egr1 in alphaT3 cells rescues activity of a transfected LHB promoter-reporter, suggesting that its transcription is dependent on EGR1 crossing a critical concentration threshold. We also show that Csda, a gene that encodes an RNA-binding protein and is a member of the cold-shock-domain (CSD) family, is expressed at higher levels in LbetaT2 compared to alphaT3 cells. Transient expression studies indicate that at least one Csd element, residing in the 3' untranslated region of Egr1 mRNA, increases activity of a chimeric pGL3 luciferase reporter vector in LbetaT2 cells. Additional experiments indicate that CSDA physically interacts with Egr1 mRNA. Furthermore, siRNA-mediated reduction of endogenous Csda mRNA attenuates GnRH regulation of a transiently transfected LHB reporter vector. Taken together, these studies suggest that CSDA contributes posttranscriptionally to GnRH-regulated expression of Egr1, thereby enabling the transcription factor to cross a critical concentration threshold necessary for maximal accumulation of Lhb mRNA in response to the neurohormone.

Translational control of gene expression in the gonadotrope

“…The general function of CSD proteins are as participants in mRNA stability and as mRNA chaperones that promote translation. In LβT2 cells CSDA is highly expressed relative to αT3-1 cells and binds to the 3’ UTR of Egr1 mRNA (Chauvin et al, 2012). Differences in CSDA expression correlate to differences in expression of EGR1.…”

Identification of driver genes and key pathways of prolactinoma predicts the therapeutic effect of genipin

“…A total of 24 genes were selected with degrees >72; EGR1, MAPK1, MYC, Bcl2 and calmodulin 1 (CALM1). EGR1, a primary response gene that encodes a zinc finger DNA-binding protein, is reported to be critical in cancer metastasis and tumor invasion (31). This gene was found to be regulated by gonadotropin-releasing hormone (GnRH) to regulate the expression of luteinizing hormone β polypeptide, one of the GnRH-responsive genes, and was revealed to be associated with prolactinoma in a previous study (31).…”

“…EGR1, a primary response gene that encodes a zinc finger DNA-binding protein, is reported to be critical in cancer metastasis and tumor invasion (31). This gene was found to be regulated by gonadotropin-releasing hormone (GnRH) to regulate the expression of luteinizing hormone β polypeptide, one of the GnRH-responsive genes, and was revealed to be associated with prolactinoma in a previous study (31). Previous studies have suggested that genipin inhibits the proliferation of various cancer cells by promoting EGR1 function, such as gastric, colon and breast cancer (32,33).…”

Μελέτη Της Γονιδιακής Έκφρασης Της Ορμόνης FSH Της Γλυκοπρωτεΐνης SHBG Και Του Υποδοχέα FSHR Σε Γυναίκες Με Πτωχή Ωοθηκική Απόκριση Που Υποβάλλονται Σε Εξωσωματική Γονιμοποίηση

“…Συγκεκριμένα, δείχθηκε σε καλλιέργειες κυττάρων LβT2 δείχθηκε ότι η Ρ 4 μπορεί να καταστείλει την έκφραση LHB mRNA μετά την πρόσδεσή της στον πυρηνικό υποδοχέα. Έλλειψη έκφρασης του LHB προκαλεί υπογονιμότητα (61).…”