title: Gonadotropin-releasing hormone pulse sensitivity of follicle-stimulating hormone-beta gene is mediated by differential expression of positive regulatory activator protein 1 factors and corepressors SKIL and TGIF1.
abstract: Gonadotropin synthesis and release is dependent on pulsatile stimulation by the hypothalamic neuropeptide GnRH. Generally, slow GnRH pulses promote FSH production, whereas rapid pulses favor LH, but the molecular mechanism underlying this pulse sensitivity is poorly understood. In this study, we developed and tested a model for FSHβ regulation in mouse LβT2 gonadotropes. By mining a previous microarray data set, we found that mRNA for positive regulators of Fshb expression, such as Fos and Jun, were up-regulated at slower pulse frequencies than a number of potential negative regulators, such as the corepressors Skil, Crem, and Tgif1. These latter corepressors reduced Fshb promoter activity whether driven by transfection of individual transcription factors or by treatment with GnRH and activin. Overexpression of binding or phosphorylation-defective ski-oncogene-like protein (SKIL) and TG interacting factor (TGIF1) mutants, however, failed to repress Fshb promoter activity. Knockdown of the endogenous repressors SKIL and TGIF1, but not cAMP response element-modulator, increased Fshb promoter activity driven by constant GnRH or activin. Chromatin immunoprecipitation analysis showed that FOS, SKIL, and TGIF1 occupy the FSHβ promoter in a cyclical manner after GnRH stimulation. Overexpression of corepressors SKIL or TGIF1 repressed induction of the Fshb promoter at the slow GnRH pulse frequency but had little effect at the fast pulse frequency. In contrast, knockdown of endogenous SKIL or TGIF1 selectively increased Fshb mRNA at the fast GnRH pulse frequency. Therefore, we propose a potential mechanism by which production of gonadotropin Fshb is modulated by positive transcription factors and negative corepressors with different pulse sensitivities.
authors.affiliation: Medical Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California 92161, USA.
authors.forename: Devendra S
authors.initials: DS
authors.lastname: Mistry
authors.forename: Rie
authors.initials: R
authors.lastname: Tsutsumi
authors.forename: Marina
authors.initials: M
authors.lastname: Fernandez
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.forename: Steven A
authors.initials: SA
authors.lastname: Cardenas
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lawson
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D000818:Animals; D056970:Co-Repressor Proteins / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; C497411:Crem protein, mouse; D037201:Follicle Stimulating Hormone, beta Subunit; D018398:Homeodomain Proteins; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D012097:Repressor Proteins; C486157:Skil protein, mouse; C490797:Tgif1 protein, mouse; D018808:Transcription Factor AP-1; D051786:Cyclic AMP Response Element Modulator; D007987:Gonadotropin-Releasing Hormone