Transcription factors regulated by cAMP in smooth muscle of the myometrium at human parturition

Abstract

Cyclic adenosine monophosphate (cAMP) contributes to maintenance of a quiescent (relaxed) state in the myometrium (i.e. uterine smooth muscle) during pregnancy, which most commonly has been attributed to activation of protein kinase A (PKA). PKA-mediated phosphorylation of cytosolic contractile apparatus components in myometrial smooth muscle cells (mSMCs) are known to promote relaxation. Additionally, PKA also regulates nuclear transcription factor (TF) activity to control expression of genes important to the labour process; these are mostly involved in actin-myosin interactions, cell-to-cell connectivity and inflammation, all of which influence mSMC transition from a quiescent to a contractile (pro-labour) phenotype. This review focuses on the evidence that cAMP modulates the activity of TFs linked to pro-labour gene expression, predominantly cAMP response element (CRE) binding TFs, nuclear factor κB (NF-κB), activator protein 1 (AP-1) family and progesterone receptors (PRs). This review also considers the more recently described exchange protein directly activated by cAMP (EPAC) that may oppose the pro-quiescent effects of PKA, as well as explores findings from other cell types that have the potential to be of novel relevance to cAMP action on TF function in the myometrium.

Keywords: bZIP transcription factors; cAMP; muscle contraction; pregnancy; signal transducers and activators of transcription; uterus.

Figure 1.. Overview of cAMP-regulated transcription factor activity in myometrial smooth muscle cells during pregnancy and labour.

Upon agonist binding to G-protein coupled receptors (GPCRs) that promote cyclic adenosine monophosphate (cAMP) signalling, Gαs dissociates from its trimeric G-protein complex to activate adenylate cyclase (AC) and thus increase cAMP synthesis. Elevation of cAMP concentrations increase the probability of cAMP to bind both regulatory subunits of each tetrameric protein kinase A (PKA) complex, which causes the dissociation and activation of both its catalytic subunits that subsequently phosphorylate proteins with exposed serine/threonine-containing motifs compatible to their active sites. These include transcription factors that bind to the cAMP response element (CRE) sequence within compatible gene promoters, such as CRE-binding protein (CREB) and CRE modulator (CREM); cAMP-dependent transcription factor 2 (ATF-2) can bind to CRE sites but is not a known PKA substrate. CREB and CREM activities have been proposed to promote expression of pro-quiescence genes, and this is potentially influenced by CREB heterodimerisation with ATF-2. PKA (via CREB) and PR-B activity can enhance expression of dual specificity phosphatase 1 (DUSP1), which dephosphorylates mitogen-activated protein kinases (MAPKs) to reduce phosphorylation of their downstream targets; these include progesterone receptor A (PR-A), which is phosphorylated at its Ser344/345 residue by c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) to promote its heterodimerisation and subsequent transrepression of PR-B. In addition to PKA, exchange protein directly activated by cAMP 1 (EPAC1) can also bind cAMP, which leads to activation of guanosine triphosphate (GTP)-bound Ras-like small GTPase 1 (Rap1); this promotes the phosphorylation activity of B-Raf to increase downstream MAPK signalling via extracellular signal-regulated kinase 1/2 (ERK1/2), JNK, SAPK and/or p38. Subsequently, activator protein 1 (AP-1) and nuclear factor κB (NF-κB) transcription factors enhance the expression of pro-labour genes, which can involve interaction with PR heterodimers. PKA and EPAC1 activities are reduced by phosphodiesterase (PDE)-mediated degradation of cAMP.