UC San Diego
Gonadotropin-releasing hormone induction of c-Jun gene expression by phosphorylation of ATF-2
- Author(s): Lindaman, Lacey Lee
- et al.
The only transcription factors induced by gonadotropin- releasing hormone known to directly regulate FSH[beta] gene expression are members of the AP-1 family. AP-1 is composed of heterodimers of homodimers of Jun and Fos family members, and of these c-Jun is the most potent transcriptional activator. Thus, understanding the molecular mechanisms of c-Jun induction by GnRH will further elucidate GnRH regulation of FSH[beta] gene expression and GnRH gonadotrope signaling pathways. GnRH can induce c-Jun protein and mRNA and GnRH induction of the c-Jun promoter maps between -70 and -61 region of the c-Jun Promoter, a region that contains a cAMP response element. The CRE site is necessary and sufficient for GnRH induction of c-Jun, and the CRE binding proteins activating factor 2 (ATF-2), phosphorylated ATF-2, and activating factor 3 (ATF-3) can bind to the c-Jun promoter. GnRH treatment induces ATF-3 and phosphorylation of ATF-2 in L[beta]T2 cells, and ATF-2 subsequently induces the c-Jun promoter and CRE element. A dominant- negative ATF-2 reduces basal expression, induction of c- Jun promoter by wild type ATF-2, and GnRH induction, therefore ATF-2 is necessary for c-Jun induction by GnRH. The known repressor ATF-3 is able to act as a repressor for c-Jun induction with ATF-2 over-expression, but it is not able to repress c-Jun induction by GnRH. However, Jun Dimerizing Protein 2 (JPD2) is able to repress ATF-2 over- expression and well as reduce GnRH induction of c-Jun thus identifying a novel player that is able to negatively feedback on GnRH regulation of c-Jun