Identification of human myometrial target genes of the cAMP pathway: the role of cAMP-response element binding (CREB) and modulator (CREMα and CREMτ2α) proteins

Abstract

AbstractcAMP-response element (CRE) binding (CREB) and modulator (CREM) proteins, activated by protein kinase A-mediated phosphorylation, bind as homo-and heterodimers to promoters containing CRE and activator protein 1 (AP-1) sites to alter target-gene expression. We have previously reported differential expression of CREB and CREM splice variants CREM and CREM 2 in human myometrium during pregnancy and labour. Via microarray studies with cultured myometrial cells stably transfected with CREB, CREM and CREM 2 cDNAs, CREB affected the expression of 958 genes; 522 being up-regulated and 436 down-regulated. CREM altered the expression of 118 genes; 71 were increased and 47 decreased. CREM 2 affected 220 genes; 148 were activated and 72 repressed. Notably, genes affected by CREB, CREM and CREM 2 belong to largely discrete groups: less than 9% were affected by more than one factor. Genes involved in regulation of cell death and apoptosis, growth and maintenance, signal transduction, physiological and developmental processes, protein kinase cascades, extracellular matrix, cytoskeleton, cell-cycle regulation, transport, and a variety of enzymes, intracellular components and nucleic acid-binding proteins have been described, many of which are involved in the modulation of myometrial activity during pregnancy and parturition.

Identification of human myometrial target genes of the c-Jun NH2-terminal kinase (JNK) pathway: the role of activating transcription factor 2 (ATF2) and a novel spliced isoform ATF2-small

“…It is therefore interesting to note the increased expression of oestrogen receptor 2 (ESR2/ESR-beta) with over-expression of ATF2, and to compare this to the detected increase in expression of the alternative oestrogen receptor 1 (ESR1/ESR-alpha) associated with over-expression of the ATF2-related bZIP transcription factor CREB in myometrial cells (Bailey et al 2004), which has been found to be prevalent in the non-pregnant myometrium but almost absent in pregnant non-labouring and spontaneous labouring tissue (Bailey et al 2000). Interestingly, a significant minority of genes found to be affected by the over-expression of ATF2 and ATF2-sm in myometrial cells in this study are also affected by CREB (Bailey et al 2004): 25% of the genes affected by ATF2, and 38% of the genes affected by ATF2-sm.…”

cAMP-responsive Element Modulator α (CREMα) Contributes to Decreased Notch-1 Expression in T Cells from Patients with Active Systemic Lupus Erythematosus (SLE)

“…Plasmids and Luciferase Assays-An expression plasmid for human CREM␣ (in the pcDNA3.1/V5-His-TOPO vector, Invitrogen) was kindly provided by G. N. Europe-Finner (Faculty of Medical Sciences, Newcastle upon Tyne, United Kingdom) (29). A 2.1-bp spanning Notch-1 reporter construct (in pGL3-Basic vector, Promega) was generated and kindly donated by M. Ruppert (University of Alabama at Birmingham) (30).…”

Possible dual roles for prostacyclin in human pregnancy and labor

“…An issue key to the current study is how myometrial hIP/PKA signaling may effect changes in the expression of SM2-MHC, h-caldesmon, calponin, a-SMA, and connexin 43. However, cAMP elevation instigates a wide variety of transcriptional events in many cells and tissue types, including myometrium (5). Given the pleiotropic nature of such cAMP-mediated regulation, one wonders whether other receptor-coupled stimuli (e.g., β-adrenergic agonists, prostaglandin E2, etc.)…”

“…In fact, early observations that the uterine environment is rich in hematopoietic growth factors/cytokines (whose expression in many cases is regulated by the ovarian sex steroid hormones 17β-estradiol and progesterone), coupled with the observation of the dynamic recruitment of diverse innate immune cells, led to the proposal that these immune cells play an important role in decidual and placental development (2,3). Among the earliest growth factors expressed in the uterus are GM-CSF and CSF-1, which regulate the myeloid system (4,5). Levels of CSF-1 synthesized by the uterine epithelium are elevated at the time of implantation and continue to climb dramatically throughout the process of placentation (4).…”