Estrogen receptor ESR1 mediates activation of ERK1/2, CREB, and ELK1 in the corpus of the epididymis

Abstract

Expression of the estrogen receptor ESR1 is higher in the corpus than it is in the initial segment/caput and cauda of the epididymis. ESR1 immunostaining in the corpus has been localized not only in the nuclei but also in the cytoplasm and apical membrane, which indicates that ESR1 plays a role in membrane-initiated signaling. The present study investigated whether ESR1 mediates the activation of rapid signaling pathways by estradiol (E 2 ) in the epididymis. We investigated the effect of E 2 and the ESR1-selective agonist (4,4 0 ,4 0 0 -(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) on the activation of extracellular signal-regulated protein kinases (ERK1/2), CREB protein, and ETS oncogene-related protein (ELK1). Treatment with PPT did not affect ERK1/2 phosphorylation in the cauda, but it rapidly increased ERK1/2 phosphorylation in the initial segment/caput and corpus of the epididymis. PPT also activated CREB and ELK1 in the corpus of the epididymis. The PPT-induced phosphorylation of ERK1/2, CREB, and ELK1 was blocked by the ESR1-selective antagonist MPP and by pretreatment with a non-receptor tyrosine kinase SRC inhibitor, an EGFR kinase inhibitor, an MEK1/2 inhibitor, and a phosphatidylinositol-3-kinase inhibitor. In conclusion, these results indicate that the corpus, which is a region with high expression of the estrogen receptor ESR1, is a major target in the epididymis for the activation of rapid signaling by E 2 . The sequence of events that follow E 2 interaction with ESR1 includes the SRC-mediated transactivation of EGFR and the phosphorylation of ERK1/2, CREB, and ELK1. This rapid estrogen signaling may modulate gene expression in the corpus of the epididymis, and it may play a role in the dynamic microenvironment of the epididymal lumen.

Estrogen and serotonin enhance stress‐induced visceral hypersensitivity in female rats by up‐regulating brain‐derived neurotrophic factor in spinal cord

“…Decrease in p‐CREB binding to BDNF promoter by ERα siRNA treatment suggests possible activation of p‐CREB by estrogen acting through ERα, which is further supported by showing that spinal infusion of estrogen increases p‐CREB. Spinal ERα activates intracellular signaling pathways that converge upon CREB 79‐81 including the MAPK pathway 62 . CREB activation by estrogen in the context of chronic stress creates a pro‐nociceptive pattern of gene expression in the spinal cord.…”

Estrogen receptor signaling mechanisms

“…Subsequent phosphorylation of transcription factors by the protein kinases mentioned above can alter their function and ability to bind to genomic sequences to affect gene expression. Examples of transcription factors that are affected by these signaling mechanisms include: Elk-1, CREB, CCAAT-enhancer-binding protein beta (C/EBPβ), the NF-κB complex, and the signal transducer and activator of transcription (STAT) family (Cavalcanti, Lucas, Lazari, & Porto, 2015; Fox, Andrade, & Shupnik, 2009; Furth, 2014; Kousteni et al, 2003; Laliotis et al, 2013; Ozes et al, 1999; Romashkova & Makarov, 1999). Thus, by activating these non-genomic to genomic mechanisms, the estrogen receptors ERα and ERβ indirectly regulate gene transcription at alternative DNA response elements, in addition to the abovementioned genomic effects involving direct binding to EREs (Figure 7).…”

Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1

“…However, the hypomethylation mechanism can not fully explain estrogen-induced FEN1 overexpression. Estrogen-induced genes expression is generally controlled by transcriptional factor Elk-1, whose phosphorylation activity is regulated by MAPK/ERK [27,28]. Bioinformatics analysis shows the presence of four potential Elk-1 binding sites and the absence of ER-binding sites in FEN1 promoter region.…”