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

Texas A&M University - Galveston, Galveston, Texas, United States
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 05/2007; 292(4):E1110-21. DOI: 10.1152/ajpendo.00373.2006
Source: PubMed


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 ( approximately 30-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.

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    • "We report here that SPHK1 is highly expressed in HESCs and further up-regulated after hormonal treatment in vitro. Other studies also reported the up-regulation of SPHK1 in the mouse uterus (Jeng et al., 2007; Mizugishi et al., 2007). These date indicate that expression of SPHK1 regulates decidualization processes possibly via increasing the growth and differentiation of HESCs. "
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    ABSTRACT: In the luteal phase, human endometrial stromal cells (HESCs) undergo proliferation, migration and differentiation during the decidualization process under the control of the ovarian steroids progesterone and estrogen. Proper decidualization of stromal cells is required for blastocyst implantation and the development of pregnancy. The proliferation, migration and differentiation of HESCs in decidualization do not require the presence of a blastocyst but are greatly accelerated during implantation. Lysophosphatidic acid (LPA) and Sphingosine-1-phosphate (S1P) are potent bioactive lysophospholipids that have critical roles in various physiological and pathophysiological processes including inflammation, angiogenesis and cancer. The expression of the enzymes involved in LPA and S1P turnover and their receptors in HESCs during decidualization has not been characterized yet. We found that the LPAR1 and LPAR6 and S1PR3 receptors are highly expressed in HESCs. LPAR1, autotaxin (ATX), an LPA producing enzyme and lipid phosphate phosphatase 3 (LPP3) were upregulated during decidualization. Interestingly, the expression of all S1P receptor subtypes and LPA receptors (LPAR2-6) mRNA was downregulated after decidualization. We found that SPHK1 is highly expressed in HESCs, and is upregulated during decidualization. S1P phosphatase SGPP1 and S1P lyase SGPL1 are highly expressed in HESCs. SGPP1 mRNA expression was significantly upregulated in decidualized HESCs. In conclusion, this study shows the first time that specific LPA and S1P receptors and their metabolizing enzymes are highly regulated in HESCs during decidualization. Furthermore, we suggest that LPAR1 receptor-mediated signaling in HESCs may be crucial in decidualization process. SPHK1 activity and high turnover of S1P and LPA might be essential for precise regulation of their signaling during decidualization of human endometrium and implantation.
    Full-text · Article · Jul 2014 · Molecular Human Reproduction
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    • "In addition, SphK1, a key enzyme for S1P production, was detected in rat glandular epithelium, vasculature and the myometrium, and was up-regulated by P4. A recent study also suggested that SphK1 involved growth and differentiation of uterine tissues during pregnancy (Jeng et al., 2007). "
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    ABSTRACT: Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two prominent signaling lysophospholipids (LPs) exerting their functions through a group of G protein-coupled receptors (GPCRs). This review covers current knowledge of the LP signaling in the function and pathology of the reproductive system. PubMed was searched up to May 2008 for papers on lysophospholipids/LPA/S1P/LPC/SPC in combination with each part of the reproductive system, such as testis/ovary/uterus. LPA and SIP are found in significant amounts in serum and other biological fluids. To date, 10 LP receptors have been identified, including LPA(1-5) and S1P(1-5). In vitro and in vivo studies from the past three decades have demonstrated or suggested the physiological functions of LP signaling in reproduction, such as spermatogenesis, male sexual function, ovarian function, fertilization, early embryo development, embryo spacing, implantation, decidualization, pregnancy maintenance and parturition, as well as pathological roles in ovary, cervix, mammary gland and prostate cancers. Receptor knock-out and other studies indicate tissue-specific and receptor-specific functions of LP signaling in reproduction. More comprehensive studies are required to define mechanisms of LP signaling and explore the potential use as a therapeutic target.
    Preview · Article · Jul 2008 · Human Reproduction Update
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    ABSTRACT: Phospholipase D (PLD) hydrolyzes phosphatidylcholine into phosphatidic acid (PA), a lipidic mediator that may act directly on cellular proteins or may be metabolized into lysophosphatidic acid (LPA). We previously showed that PLD contributed to the mitogenic effect of endothelin-1 (ET-1) in a leiomyoma cell line (ELT3 cells). In this work, we tested the ability of exogenous PA and PLD from Streptomyces chromofuscus (scPLD) to reproduce the effect of endogenous PLD in ELT3 cells and the possibility that these agents acted through LPA formation. We found that PA, scPLD, and LPA stimulated thymidine incorporation. LPA and scPLD induced extracellular signal-regulated kinase (ERK(1/2)) mitogen-activated protein kinase activation. Using Ki16425, an LPA(1)/LPA(3) receptor antagonist and small interfering RNA targeting LPA(1) receptor, we demonstrated that scPLD acted through LPA production and LPA(1) receptor activation. We found that scPLD induced LPA production by hydrolyzing lysophosphatidylcholine through its lysophospholipase D (lysoPLD) activity. Autotaxin (ATX), a naturally occurring lysoPLD, reproduced the effects of scPLD. By contrast, endogenous PLD stimulated by ET-1 failed to produce LPA. These results demonstrate that scPLD stimulated ELT3 cell proliferation by an LPA-dependent mechanism, different from that triggered by endogenous PLD. These data suggest that in vivo, an extracellular lysoPLD such as ATX may participate in leiomyoma growth through local LPA formation.
    Full-text · Article · Mar 2008 · The Journal of Lipid Research
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