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Elk‐1, CREB, and MKP‐1 regulate Egr‐1 expression in gonadotropin‐releasing hormone stimulated gonadotrophs
Author(s) -
Mayer Sabine I.,
Willars Gary B.,
Nishida Eisuke,
Thiel Gerald
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21927
Subject(s) - gonadotropic cell , creb , biology , microbiology and biotechnology , signal transduction , transcription factor , endocrinology , medicine , pituitary gland , biochemistry , gene , hormone
Stimulation of gonadotropin‐releasing hormone (GnRH) receptors with the GnRH analogue buserelin enhances expression of the zinc finger transcription factor Egr‐1 in a pituitary gonadotroph cell line. The signaling cascade is blocked by overexpression of MAP kinase phosphatase‐1 that dephosphorylates extracellular signal‐regulated protein kinase in the nucleus. Chromatin immunoprecipitation experiments revealed that the phosphorylated form of Elk‐1, a key regulator of gene transcription driven by serum response element (SRE), binds to the 5′‐upstream region of the Egr‐1 gene in buserelin‐stimulated gonadotrophs. Expression of a dominant‐negative mutant of Elk‐1 completely blocked Egr‐1 expression, indicating that Elk‐1 connects the intracellular signaling cascade elicited by activation of GnRH receptors with transcription of the Egr‐1 gene. GnRH receptor activation additionally induced the phosphorylation of CREB, which in its phosphorylated form bound to the Egr‐1 gene. Expression of a dominant‐negative mutant of CREB reduced GnRH receptor‐induced upregulation of Egr‐1 expression, indicating that CREB plays a role in the signaling pathway that regulates Egr‐1 expression in gonadotrophs. We further identified the genes encoding basic fibroblast growth factor, tumor necrosis factor α, and transforming growth factor β as bona fide target genes of Egr‐1 in gonadotrophs. The analysis of gonadotroph cells that express—in addition to GnRH receptors—muscarinic M 3 acetylcholine receptors revealed that the nuclear events connecting GnRH receptors and muscarinic M 3 acetylcholine receptors with the Egr‐1 gene are indistinguishable. J. Cell. Biochem. 105: 1267–1278, 2008. © 2008 Wiley‐Liss, Inc.