{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:13:12Z","timestamp":1784164392050,"version":"3.55.0"},"reference-count":50,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 LH\u03b2 and FSH\u03b2 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 FHS\u03b2 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.<\/jats:p>","DOI":"10.1210\/me.2012-1168","type":"journal-article","created":{"date-parts":[[2012,12,29]],"date-time":"2012-12-29T07:11:30Z","timestamp":1356765090000},"page":"253-265","source":"Crossref","is-referenced-by-count":20,"title":["GnRH Increases c-Fos Half-Life Contributing to Higher FSH\u03b2 Induction"],"prefix":"10.1210","volume":"27","author":[{"given":"Gaddameedi R.","family":"Reddy","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey L.","family":"Lindaman","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djurdjica","family":"Coss","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 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phosphorylation of SRF by the calcium\/calmodulin kinase II pathway.","volume":"25","author":"Ely","year":"2011","journal-title":"Mol Endocrinol"},{"key":"2020071613324583200_B39","doi-asserted-by":"crossref","first-page":"18842","DOI":"10.1074\/jbc.M500620200","article-title":"Phosphorylation of c-Fos by members of the p38 MAPK family. Role in the AP-1 response to UV light.","volume":"280","author":"Tanos","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071613324583200_B40","doi-asserted-by":"crossref","first-page":"7030","DOI":"10.1128\/MCB.23.19.7030-7043.2003","article-title":"Phosphorylation of the carboxyl-terminal transactivation domain of c-Fos by extracellular signal-regulated kinase mediates the transcriptional activation of AP-1 and cellular transformation induced by platelet-derived growth factor.","volume":"23","author":"Monje","year":"2003","journal-title":"Mol Cell Biol"},{"key":"2020071613324583200_B41","doi-asserted-by":"crossref","first-page":"33567","DOI":"10.1074\/jbc.M404013200","article-title":"c-Fos phosphorylation induced by H2O2 prevents proteasomal degradation of c-Fos in cardiomyocytes.","volume":"279","author":"Coronella-Wood","year":"2004","journal-title":"J Biol Chem"},{"key":"2020071613324583200_B42","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1126\/science.1127085","article-title":"Proteasome-independent functions of ubiquitin in endocytosis and signaling.","volume":"315","author":"Mukhopadhyay","year":"2007","journal-title":"Science"},{"key":"2020071613324583200_B43","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1002\/bies.20447","article-title":"20S proteasomes and protein degradation \u201dby default\u201c.","volume":"28","author":"Asher","year":"2006","journal-title":"Bioessays"},{"key":"2020071613324583200_B44","doi-asserted-by":"crossref","first-page":"4930","DOI":"10.1074\/jbc.271.9.4930","article-title":"Ubiquitinylation of transcription factors c-Jun and c-Fos using reconstituted ubiquitinylating enzymes.","volume":"271","author":"Hermida-Matsumoto","year":"1996","journal-title":"J Biol Chem"},{"key":"2020071613324583200_B45","doi-asserted-by":"crossref","first-page":"6964","DOI":"10.1128\/MCB.25.16.6964-6979.2005","article-title":"Down-regulation of c-Fos\/c-Jun AP-1 dimer activity by sumoylation.","volume":"25","author":"Bossis","year":"2005","journal-title":"Mol Cell Biol"},{"key":"2020071613324583200_B46","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.1093\/nar\/22.24.5173","article-title":"Phosphorylation of the c-Fos and c-Jun HOB1 motif stimulates its activation capacity.","volume":"22","author":"Bannister","year":"1994","journal-title":"Nucleic Acids Res"},{"key":"2020071613324583200_B47","doi-asserted-by":"crossref","first-page":"7563","DOI":"10.1038\/sj.onc.1204880","article-title":"Identification of a C-terminal tripeptide motif involved in the control of rapid proteasomal degradation of c-Fos proto-oncoprotein during the G(0)-to-S phase transition.","volume":"20","author":"Acquaviva","year":"2001","journal-title":"Oncogene"},{"key":"2020071613324583200_B48","first-page":"1493","article-title":"Phosphorylation of c-Fos at the C-terminus enhances its transforming activity.","volume":"12","author":"Chen","year":"1996","journal-title":"Oncogene"},{"key":"2020071613324583200_B49","doi-asserted-by":"crossref","first-page":"12991","DOI":"10.1016\/S0021-9258(18)42372-1","article-title":"Protein phosphatase inhibitors induce the sustained expression of the Egr-1 gene and the hyperphosphorylation of its gene product.","volume":"267","author":"Cao","year":"1992","journal-title":"J Biol Chem"},{"key":"2020071613324583200_B50","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/emboj.2008.238","article-title":"PTEN regulation by Akt-EGR1-ARF-PTEN axis.","volume":"28","author":"Yu","year":"2009","journal-title":"EMBO J"}],"container-title":["Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/27\/2\/253\/10721863\/mend0253.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/27\/2\/253\/10721863\/mend0253.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T20:37:04Z","timestamp":1644007024000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mend\/article\/27\/2\/253\/2615055"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,1]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2013,2,1]]}},"URL":"https:\/\/doi.org\/10.1210\/me.2012-1168","relation":{},"ISSN":["0888-8809","1944-9917"],"issn-type":[{"value":"0888-8809","type":"print"},{"value":"1944-9917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,1]]}}}