Synergistic Regulation of Human Oxytocin Receptor Promoter by CCAAT/ Enhancer-Binding Protein and RELA1

Abstract

Uterine activation is associated with increased oxytocin receptor (OXTR) expression and myometrial sensitivity to oxytocin. The OXTR promoter contains binding sites for CCAAT/enhancer-binding protein (CEBP) and nuclear factor-kappa B p65 (RELA). RELA and CEBP beta (CEBPB) play a synergistic role in OXTR promoter activation. We created deletions in a DNA construct consisting of 850 bp upstream of the transcription start site linked to luc reporter to identify the CIS element of the OXTR promoter responsible for the synergistic activation by RELA and CEBPB. Deletion from -712 to -692 bp eliminated synergy, demonstrating that the critical region lies within these 20 bp. Binding studies showed that this sequence binds both RELA and CEBPB. The 20-bp critical region for synergistic activation of OXTR requires full-length RELA but only the basic leucine zipper domain of CEBPB.

Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways

“…Taken together, it would let us suggest that PGF2A stimulates PTGS2 through different signalling pathways in different types of cells. Some studies have demonstrated that NFkB activation induces OTR expression in myometrium (Khanjani et al 2011). Herein, we found that NFkB was not involved in PGF2A stimulation of OTR in myometrial cells.…”

The role of NFκB in the three stages of pregnancy – implantation, maintenance, and labour: a review article

“…Khanjani et al. propose that oxytocin receptor gene regulation depends on the synergistic cooperation of NF κ B and CEBP, and that the cooperation and binding of both transcription factors to the OXTR gene is increased by IL‐1 β , the expression of which is also regulated by NF κ B …”

“…85 Khanjani et al propose that oxytocin receptor gene regulation depends on the synergistic cooperation of NFjB and CEBP, and that the cooperation and binding of both transcription factors to the OXTR gene is increased by IL-1b, the expression of which is also regulated by NFjB. 86 To summarise, NFjB has been implicated in numerous processes related to human labour. Literature data indicate that an elevated NFjB level at term is linked with the following processes: (1) activation of metalloproteinases, implicated in the degradation of fetal membranes as well as in the preparation of the reproductive system for an influx of inflammatory cells; (2) regulation of the inflammatory response, which allows the stimulation of COX-2 and prostaglandins; (3) control of COX-2 gene expression; and (4) regulation of gene expression of contraction-associated protein and the oxytocin receptor.…”

Progesterone inhibition of oxytocin signaling in endometrium

“…But, regulation of OXTR gene function by P in pregnant myometrium is most likely indirect via immunosuppressive actions of P [as reviewed by Arck et al (2007)]. Recently, binding sites for nuclear factor-kappa B p65 (RELA) and CCAAT/enhancer-binding protein (CEBP) were identified in the human OXTR gene promotor region (Khanjani et al, 2011). Expression of CEBP and RELA are increased in inflammatory responses (Adams et al, 2000), and mediators of both are increased in near-term myometrium of women (Khanjani et al, 2011).…”