Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences

Abstract

Jeng YJ, Suarez VR, Izban MG, Wang HQ, Soloff MS. Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences. Am J Physiol Endocrinol Metab 292: E1110 -E1121, 2007. First published December 12, 2006; doi:10.1152/ajpendo.00373.2006.-Sphingosine 1-phosphate (Sph-1-P), a product of sphingomyelin metabolism, can act via a family of cognate G protein-coupled receptors or as an intracellular second messenger for agonists acting through their membrane receptors. In view of the general growth promoting and developmental effects of Sph-1-P on target cells, we hypothesized that it plays a role in adaptation of the uterus to pregnancy. We analyzed its potential role and that of the related lysophospholipid lysophosphatidic acid in the pregnant rat uterus by examining changes in mRNA levels of cognate receptors and enzymes involved in their turnover. Of these, only sphingosine kinase-1 (SphK1) was markedly changed (ϳ30-fold increase), being localized in the glandular epithelium, vasculature, and the myometrium. Uterine SphK1 mRNA and protein levels paralleled those of serum progesterone, and treatment with progesterone or an antagonist elevated or reduced SphK1 mRNA expression, respectively. Progesterone also increased SphK1 mRNA steady-state levels in a rat myometrial/leiomyoma cell line (ELT3). Overexpressing human SphK1 in these cells resulted in increased levels of the cell cycle regulator cyclin D1 and increased myosin light-chain phosphorylation. Ectopic expression of SphK1 also resulted in increased proliferation rates, possibly in conjunction with increased cyclin D1 expression. These studies suggest that the uterine expression of SphK1 mediates processes involved in growth and differentiation of uterine tissues during pregnancy. ELT3 cells; myosin light-chain phosphorylation; cyclin D1; lysophospholipids; sphingosine 1-phosphate; sphingosine-1-phosphate lyase THE BIOACTIVE LYSOPHOSPHOLIPIDS sphingosine 1-phosphate (Sph-1-P) and lysophosphatidic acid (LPA) are growth factors that act through a family of G protein-coupled receptors (GPCRs), S1P 1 through S1P 5 and LPA 1 through LPA 4 , respectively (25), causing a broad array of effects on target cells, including cell proliferation, survival, migration, adhesion molecule expression, and morphogenesis (26,31,44,47,52). Sph-1-P also plays a role in vasculogenesis in the mouse embryo (4, 27). Both lysophospholipids increase myosin lightchain phosphorylation in platelets and endothelial cells (10, 37) by inhibiting myosin light-chain phosphatase (43). They also stimulate DNA synthesis in human myometrial cells in primary culture (20,32). Platelets are the major source of circulating Sph-1-P and LPA, releasing the lysophospholipids in response to prothrombotic stimuli (47, 54). Circulating Sph-1-P also arises by constitutive secretion by cells of hemangioblastic lineage, such as monocytes, and by mast, endothelial, and red blood cells (54).Intracellular Sph-1-P is synthesized by a variety of cell types and acts as a...

Signaling Pathways Involved in Sphingosine Kinase Activation and Sphingosine-1-Phosphate Release in Rat Myometrium in Late Pregnancy: Role in the Induction of Cyclooxygenase 2

“…A recent study showed that in uterus, SphK1 mRNA and protein increased at late pregnancy (23). However, no significant pregnancy-related changes in SphK2 mRNA levels were observed in this study (23). By contrast, we demonstrated that in myometrial tissues, not only the levels of SphK2 protein, but also its activity, increased at the end of gestation.…”

“…These findings suggested that SphK1/2 protein synthesis may be similarly controlled in the myometrium at the end of gestation. A recent study showed that in uterus, SphK1 mRNA and protein increased at late pregnancy (23). However, no significant pregnancy-related changes in SphK2 mRNA levels were observed in this study (23).…”

“…Protein levels were low at midgestation (d 12), markedly increased at d 19, and declined to low levels in the postpartum period. The up-regulation of SphK1 in myometrium at d 19 of gestation is consistent with findings from the recent study by Jeng et al (23) performed in rat uterus.…”

“…COX2 levels are regulated by PKC, MAPKs, ERK, and p38 (22). Recently, Jeng et al (23) demonstrated that SphK1 is up-regulated by progesterone, a steroid hormone playing an important role in uterus physiology during gestation.…”

Role of lysophosphatidic acid in the regulation of uterine leiomyoma cell proliferation by phospholipase D and autotaxin

“…Furthermore, we recently reported that in ELT3 cells, SphK1 and S1P exerted an antiapoptotic effect (4) and that exogenous S1P stimulated DNA synthesis (unpublished results). In agreement with these observations, Jeng et al (45) found that overexpression of SphK1 in ELT3 cells increased cell proliferation. In light of these data, it became possible to postulate that the SphK1/S1P pathway may be one mechanism by which endogenous PA contributes to ET-1-mediated ERK 1/2 activation and cell proliferation in ELT3 cells.…”