title: GnRH increases c-Fos half-life contributing to higher FSHβ induction.
abstract: GnRH is a potent hypothalamic regulator of gonadotropin hormones, LH and FSH, which are both expressed within the pituitary gonadotrope and are necessary for the stimulation of gametogenesis and steroidogenesis in the gonads. Differential regulation of LH and FSH, which is essential for reproductive fitness, is achieved, in part, through the varying of GnRH pulse frequency. However, the mechanism controlling the increase in FSH during the periods of low GnRH has not been elucidated. Here, we uncover another level of regulation by GnRH that contributes to differential expression of the gonadotropins and may play an important role for the generation of the secondary rise of FSH that stimulates folliculogenesis. GnRH stimulates LHβ and FSHβ subunit transcription via induction of the immediate early genes, Egr1 and c-Fos, respectively. Here, we determined that GnRH induces rapidly both Egr1 and c-Fos, but specifically decreases the rate of c-Fos degradation. In particular, GnRH modulates the rate of c-Fos protein turnover by inducing c-Fos phosphorylation through the ERK1/2 pathway. This extends the half-life of c-Fos, which is normally rapidly degraded. Confirming the role of phosphorylation in promoting increased protein activity, we show that a c-Fos mutant that cannot be phosphorylated by GnRH induces lower expression of the FHSβ promoter than wild-type c-Fos. Our studies expand upon the role of GnRH in the regulation of gonadotropin gene expression by highlighting the role of c-Fos posttranslational modification that may cause higher levels of FSH during the time of low GnRH pulse frequency to stimulate follicular growth.
authors.affiliation: Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093-0674, USA.
authors.forename: Gaddameedi R
authors.initials: GR
authors.lastname: Reddy
authors.forename: Changchuan
authors.initials: C
authors.lastname: Xie
authors.forename: Lacey L
authors.initials: LL
authors.lastname: Lindaman
authors.forename: Djurdjica
authors.initials: D
authors.lastname: Coss
mesh_terms: D000818:Animals; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D037201:Follicle Stimulating Hormone, beta Subunit / Q000096:biosynthesis*; D015870:Gene Expression; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006062:Gonadotropins / Q000096:biosynthesis*; D037101:Luteinizing Hormone, beta Subunit / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009154:Mutation; D006080:Ovarian Follicle / Q000378:metabolism; D010766:Phosphorylation; D010902:Pituitary Gland / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D037201:Follicle Stimulating Hormone, beta Subunit; D006062:Gonadotropins; D037101:Luteinizing Hormone, beta Subunit; D016760:Proto-Oncogene Proteins c-fos; D007987:Gonadotropin-Releasing Hormone; D048049:Extracellular Signal-Regulated MAP Kinases