Prostaglandin E₂ Induces Fibroblast Growth Factor 9 via EP3-Dependent Protein Kinase Cδ and Elk-1 Signaling

Abstract

Fibroblast growth factor 9 (FGF-9) is a potent mitogen that controls the proper development of many tissues and organs. In contrast, aberrant expression of FGF-9 also results in the evolution of many human diseases, such as cancers and endometriosis. Despite its vital function being reported, the cellular and molecular mechanisms responsible for the regulation of FGF-9 expression are mostly unknown. We report here that prostaglandin E 2 (PGE 2 ) induces expression of FGF-9, which promotes endometriotic stromal cell proliferation, through the EP3 receptor-activated protein kinase C␦ (PKC␦) signaling pathway. Activation of PKC␦ leads to phosphorylation of ERK1/2, and the transcription factor Elk-1 thereby promotes transcription of FGF-9. Two Elk-1 cis-binding sites located at nucleotides ؊1324 to ؊1329 and ؊1046 to ؊1051 of the human FGF-9 promoter are identified as crucial for mediating PGE 2 actions. Collectively, we demonstrate, for the first time, that PGE 2 can directly induce FGF-9 expression via a novel signaling pathway involving EP3, PKC␦, and a member of the ETS domain-containing transcription factor superfamily in primary human endometriotic stromal cells. Our findings may also provide a molecular framework for considering roles for PGE 2 in FGF-9-related embryonic development and/or human diseases.

NFAT and CREB Regulate Kaposi's Sarcoma-Associated Herpesvirus-Induced Cyclooxygenase 2 (COX-2)

“…PGE 2 autoregulates COX-2 promoter activation and gene expression. Since KSHV infection-induced PGE 2 can initiate multiple signaling cascades (JNK-1, ERK1/2, PKC, PI3K-AKT, HPK1, and Src), second messengers, including cAMP, calcium (Ca 2ϩ ), and reactive oxygen species, in an autocrine/ paracrine manner by binding to its specific G-protein-coupled receptors (EP receptors) (3,4,6,16,18,27,32,33,35,37,38,46,52,73,77), we tested the role of exogenous PGE 2 in COX-2 promoter and COX-2 gene expression ( Fig. 2A and B).…”

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E2 in Conscious Rats

“…Further, nNOSderived nitric oxide contributes to ROS generation by interacting with the superoxide radical to produce peroxynitrite (Beckman et al, 1990), and to L-glutamate release (McNaught and Brown, 1998;Bal-Price et al, 2002). The involvement of the ERK1/2 pathway in PGE 2 -EP3 receptor-mediated signaling in other models (Chuang et al, 2006;Nicola et al, 2008) presented a rationale for investigating this pathway in the current study. Consistent with our hypothesis, intra-RVLM PGE 2 increased local ERK1/2 and nNOS phosphorylation (Fig.…”

“…Equally important, there are no studies on a potential BP role for PGE 2 -EP3 receptor signaling in the RVLM, a major brain stem cardiovascular regulatory area. We reasoned that, if PGE 2 -evoked increases in NOX activity , c-Fos expression (Lacroix et al, 1996;Zhang et al, 2011), and ERK1/2 pathway activation (Chuang et al, 2006) occur in the RVLM, they may uncover a new role for RVLM PGE 2 , because triggering these molecular mechanisms in the RVLM causes sympathoexcitation and BP increase Minson et al, 1994;Ibrahim and Abdel-Rahman, 2012;Chen et al, 2013). Therefore, we used a multilevel experimental approach to investigate these novel and interrelated possibilities.…”

“…Additional molecular events implicated in these responses are the activation (phosphorylation) of extracellular signal-regulated kinase 1/2 (ERK1/2) and neuronal nitric oxide synthase (nNOS) as well as NOX activation (Busnardo et al, 2010;Koriauli et al, 2015;Korotkov et al, 2015). Importantly, these biochemical responses have been implicated in PGE 2 -mediated inflammation/ oxidative stress in different cell types (Chuang et al, 2006;Romero et al, 2011;Wang et al, 2013). Whether PGE 2 triggers these biochemical responses in the RVLM and the implicated EP receptor subtype(s) have not been investigated.…”

Involvement of Prostaglandins in the Pathophysiology of Endometriosis

“…In the same study by Wing and coworkers, it was observed that not only FGF-9 is regulated by E 2, but also, FGF receptors 2IIIc and 3IIIc. More recently, a study revealed that PGE 2 , acting through its receptor EP3 induces the expression of FGF-9 in a dose dependent manner in endometriotic cells in vitro (Chuang et al, 2006) (Figure 2). …”