GnRH Induces the c-Fos Gene via Phosphorylation of SRF by the Calcium/Calmodulin Kinase II Pathway

Abstract

Despite extensive studies on GnRH regulation of the gonadotropin subunit genes, very little is known about mechanism of induction of intermediary immediate early genes, such as c-Fos, that are direct targets of GnRH signaling and that upon induction, activate transcription of gonadotropin genes. Although c-Fos is induced by a variety of stimuli in other cell types, in the gonadotropes, only GnRH induces c-Fos and through it FSHβ. Thus, understanding the specificity of c-Fos induction by GnRH will provide insight into GnRH regulation of FSHβ gene expression. GnRH induction of c-Fos in LβT2 cells requires the serum response factor (SRF)-binding site, but not the Ets/ELK1 site. This is in contrast to c-Fos induction by growth factors in other cells, which activate c-Fos transcription via phosphorylation of ELK1 and require the ELK1-binding site. The SRF site alone is sufficient for induction by GnRH, whereas induction by 12-tetradecanoylphorbol-13-acetate (TPA) requires both the ELK1 and SRF sites. Although ELK1 site is not required, upon GnRH stimulation, ELK1 interacts with SRF and is recruited to the SRF site. GnRH phosphorylates ELK1 through ERK1/2 and p38 MAPK, which correlates with the signaling pathways necessary for c-Fos and FSHβ induction. GnRH also causes phosphorylation of SRF through calmodulin-dependent kinase II (CamKII), which leads to increased binding to its site. CamKII activation is sufficient for phosphorylation of SRF and for induction of the c-Fos gene through the SRF site. Thus, GnRH uses a combination of growth factor signaling and the CamKII pathway to induce c-Fos to regulate FSHβ gene expression in gonadotrope cells.

Cell Excitability Necessary for Male Mating Behavior inCaenorhabditis elegansIs Coordinated by Interactions Between Big Current and Ether-A-Go-Go Family K+ Channels

“…documented (Li et al 2010;Ely et al 2011;Oruganti et al 2011), especially in cardiac muscle (Zhang et al 2004;Backs et al 2006;Little et al 2007). In C. elegans, it is possible CaMKII is regulating the transcription of slo-1, egl-2, and unc-103, since all three transcript levels are decreased in a CaMKII/unc-43(lf) mutant.…”

Acrolein-induced inflammatory signaling in vascular smooth muscle cells requires activation of serum response factor (SRF) and NFκB

“…Generation of ROS, increased intracellular calcium level and damage to SMCs have been proposed as some of the mechanisms behind acrolein toxicity [50,51] . Because it has been well established that both ROS and increased intracellular calcium can up-regulate SRF [52,53] , it is not surprising to see increased SRF expression in acrolein toxicity.…”

“…Unregulated transcription of NF κ B has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development [52,54,55] . NF κ B can induce production of cytokines, chemokines, effector molecules of immunity and pro-survival factors and regulates many genes involved in vascular physiopathology.…”

c-JUN Dimerization Protein 2 (JDP2) Is a Transcriptional Repressor of Follicle-stimulating Hormone β (FSHβ) and Is Required for Preventing Premature Reproductive Senescence in Female Mice

“…Prototypical members c-FOS and c-JUN are activated rapidly and transiently and exhibit a very short half-life to bring forth very tight temporal regulation of target genes (23). We also determined that GNRH specifically induces c-FOS (24) and c-JUN (25) transcription in the mature gonadotrope cells, whereas other hormones and stimuli that activate these genes in other cell types are not sufficient to induce AP-1 in the gonadotrope. c-FOS is not present without stimulus in quiescent cells and is more strictly regulated, both at the transcriptional and posttranslational level by GNRH, whereas c-JUN has detectable basal expression and is induced 6-fold by GNRH (26).…”