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Jonathan Pham Department of Pathology, University of California San Diego, La Jolla, California, USA
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA

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Kanaga Arul Nambi Rajan Department of Pathology, University of California San Diego, La Jolla, California, USA
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA

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Ping Li Department of Pathology, Medical School of Jinan University, Guangzhou, China

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Mana M Parast Department of Pathology, University of California San Diego, La Jolla, California, USA
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA

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Placental development is important for proper in utero growth and development of the fetus, as well as maternal well-being during pregnancy. Abnormal differentiation of placental epithelial cells, called trophoblast, is at the root of multiple pregnancy complications, including miscarriage, the maternal hypertensive disorder preeclampsia and intrauterine growth restriction. The ligand-activated nuclear receptor, PPARγ, and nutrient sensor, Sirtuin-1, both play a role in numerous pathways important to cell survival and differentiation, metabolism and inflammation. However, each has also been identified as a key player in trophoblast differentiation and placental development. This review details these studies, and also describes how various stressors, including hypoxia and inflammation, alter the expression or activity of PPARγ and Sirtuin-1, thereby contributing to placenta-based pregnancy complications.

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E. K. Asem
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M. Li
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B. K. Tsang
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ABSTRACT

Several hormone agonists exert their physiological actions by triggering an inositol phospholipid—Ca2+ signalling cascade and cytosolic alkalinization. Although calcium ionophores have been used extensively to probe the role of Ca2+ in the regulation of steroidogenesis in granulosa cells, the precise relationship between changes in intracellular Ca2+ (Ca2+ i) and pH (pHi) is unclear. In the present study we have used a fluorescent pH indicator, 2′7′-bis-(2-carboxyethyl)-5(and-6)-carboxyfluorescein, to examine the influence of two Ca2+ ionophores, ionomycin and 4-Bromo-A23187 (4-Br-A23187), on pHi in chicken granulosa cells. Chicken granulosa cells from the largest preovulatory follicle were incubated with Ca2+ ionophores (0–2 μm) and/or inhibitors of Na+/H+ antiport (amiloride, dimethylamiloride and ethylisopropyl amiloride; 0·5, 5 and 50 μm respectively) in the presence of Na+ (or choline+; 0–144 mm) and/or Ca2+ (0–10 mm). Ionomycin or 4-Br-A23187 elicited a rapid and sustained cytosolic alkalinization. The magnitude of increase in pHi was dependent on the concentration of the Ca2+ ionophore and the presence of extracellular Ca2+ but independent of extracellular Na+. Pretreatment of the cells with amiloride or its analogues failed to affect the increase in pHi induced by the Ca2+ ionophores significantly. These findings demonstrate that, in addition to their widely reported effects on Ca2+ i redistribution in granulosa cells, 4-Br-A23187 and ionomycin cause Ca2+-dependent cytosolic alkalinization. This action of the Ca2+ ionophores is independent of the Na+/H+ antiport. Caution must be exercised in using Ca2+ ionophores as probes to define the role of Ca2+ in the regulation of granulosa cell function.

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G Pelletier
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V Luu-The
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M El-Alfy
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S Li
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F Labrie
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The subcellular distribution of steroidogenic enzymes has so far been studied mostly in classical endocrine glands and in the placenta. In the peripheral intracrine organs which synthesize sex steroids there is no indication about the organelles which contain the enzymes involved in steroid biosynthesis. We have thus investigated the subcellular localization of two enzymes involved in the production of sex steroids, namely 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Using specific antibodies to these enzymes, we conducted immunoelectron microscopic studies in two peripheral tissues, namely the human prostate and mammary gland. In the prostate, immunolabelling for both 3beta-HSD and type 5 17beta-HSD was detected in the basal cells of the tube-alveoli as well as in fibroblasts and endothelial cells lining the blood vessels. In all the labelled cell types, the gold particles were distributed throughout the cytoplasm. No obvious association with any specific organelle could be observed, although some concentration of gold particles was occasionally found over bundles of microfilaments. In mammary gland sections immunolabelled for 3beta-HSD or type 5 17beta-HSD localization, labelling was observed in the cytoplasm of the secretory epithelial cells in both the acini and terminal ducts. Immunolabelling was also found in the endothelial cells as well as in fibroblasts in stroma and blood vessels. The gold particles were not detected over any organelles, except with the occasional accumulation of gold particles over microfilaments. The present data on the localization of two steroidogenic enzymes leading to the synthesis of testosterone indicate that these enzymes are located not only in epithelial cells but also in stromal and endothelial cells in both tissues studied. The absence of any association of the enzymes with membrane-bound organelles appears as a common finding in the reactive cell types of two peripheral tissues.

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R Sridaran
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GH Philip
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H Li
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M Culty
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Z Liu
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DM Stocco
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V Papadopoulos
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We have demonstrated that continuous administration of a gonadotropin-releasing hormone agonist (GnRH-Ag) suppresses luteal steroidogenesis in the pregnant rat. We further demonstrated that the peripheral-type benzodiazepine receptor (PBR) and the steroidogenic acute regulatory protein (StAR) play key roles in cholesterol transport leading to steroidogenesis. The purpose of this study was to understand the cellular and molecular mechanisms involved in the suppression of luteal steroidogenesis leading to a fall in serum progesterone levels in GnRH-Ag-treated rats during early pregnancy. Pregnant rats were treated individually starting on day 8 of pregnancy with 5 microgram/day GnRH-Ag using an osmotic minipump. Sham-operated control rats received no treatment. At 0, 4, 8 and 24 h after initiation of the treatment, rats were killed and corpora lutea (CL) were removed for PBR mRNA, protein and radioligand binding analyses, immunoblot 1-D gel analysis of StAR, P450 scc and 3beta-hydroxysteroid dehydrogenase as well as 2-D gel analysis of StAR. The treatment decreased the luteal PBR mRNA expression at all time periods starting at 4 h compared with that in corresponding sham controls. GnRH-Ag also reduced, in the CL, the PBR protein/ligand binding, the StAR protein and P450 scc protein and its activity as early as 8 h after the treatment and they remained low compared with those in corresponding sham controls. The data from 2-D gel studies suggest that the majority of the decrease in StAR protein appears to be in the phosphorylated forms of StAR. Thus, we have demonstrated, for the first time, the presence of PBR and StAR in the pregnant rat CL and that the coordinated suppression of these proteins involved in the mitochondrial cholesterol transport along with P450 scc by GnRH-Ag leads to reduced ovarian steroidogenesis.

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S L Li
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C Godson
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E Roche
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S J Zhao
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M Prentki
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W Schlegel
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ABSTRACT

The role of cytosolic free Ca2+ ([Ca2+]i) in the induction of the immediate early gene c-fos by TRH or by phorbol 12-myristate 13-acetate (PMA) was studied in the clonal pituitary cell line GH4C1. It was found that c-fos mRNA levels were rapidly and transiently increased by TRH at physiological concentrations (1–100 nm). The effect of TRH was dependent on a rise in [Ca2+]i, and TRH stimulation of Ca2+ influx was essential for c-fos induction. Cell depolarization with K+, which produces a [Ca2+]i rise by soliciting Ca2+ influx via voltage-gated Ca2+ channels, was insufficient to induce c-fos. Blockade or downregulation of protein kinase C (PKC) strongly attenuated TRH stimulation of c-fos expression. Direct stimulation of PKC by PMA raised c-fos mRNA levels, but only under conditions permitting Ca2+ influx. We conclude that TRH induces c-fos mRNA by a mechanism dependent on PKC activation and on Ca2+ influx. The essential role of Ca2+ influx for PMA stimulation of c-fos mRNA suggests a novel pathway linking PKC stimulation to early gene expression.

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Y-L Zhao Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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W-D Han Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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Q Li Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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Y-M Mu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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X-C Lu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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L Yu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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H-J Song Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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X Li Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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J-M Lu Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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C-Y Pan Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Endocrinology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China
Department of Hematology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China

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LRP16 gene expression is induced by 17-βestradiol (E2) via estrogen receptor alpha (ERα) in MCF-7 human breast cancer cells. A previous study also demonstrated that ectopic expression of LRP16 gene promoted MCF-7 cell proliferation. To explore the mechanism of hormone-induced LRP16 gene expression, the LRP16 gene promoter region (−2600 to −24 bp upstream of the LRP16 gene translation starting site) was analyzed in the present study by using different 5′-truncated constructs, and a luciferase reporter. The 5′-flanking sequence of −676 to −24 bp (pGL3-S5) was found to be E2-responsive. After exchange of the fragment from −213 to −24 bp with the TK gene proximal promoter region in pGL3-S5, E2 still induced reporter gene activity in MCF-7 and HeLa cells. Sequence analysis showed that the pGL3-S6 (−676 to −214) sequence contains two motifs that may contribute to E2-induced transactivation; namely, an estrogen-responsive element (ERE) half-site/Sp1 at −246 to −227 bp and an E-box site at −225 to −219 bp. Further deletion and mutation analysis of these two motifs indicated that both the 1/2 ERE and Sp1 binding sites were required for E2 action, while E-box deletion did not affect the luciferase activity in MCF-7 and HeLa cells. The results of gel mobility shift and chromatin immunoprecipitation assays confirmed that both ERαand Sp1 were required for hormone-induced transactivation, which involved both ERαand Sp1 directly binding to DNA. Taken together, these findings suggest that ERαand Sp1 play a role in activation of the human LRP16 gene promoter.

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FY Diao
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M Xu
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Y Hu
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J Li
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Z Xu
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M Lin
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L Wang
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Y Zhou
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Z Zhou
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J Liu
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J Sha
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Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders; it is characterized by polycystic ovaries, hyperandrogenism and chronic anovulation. To obtain a global view of those genes that might be involved in the development of this complex clinical disorder, we used recently developed cDNA microarray technology to compare differential gene expressions between normal human ovary and ovaries from PCOS patients. A total of 9216 clones randomly selected from a commercial human ovary cDNA library were screened. Among them, 290 clones showed differential expressions, including 119 known genes and 100 known or unknown expressed sequence tags (ESTs). Among 119 known genes, 88 were upregulated and 31 downregulated in the PCOS ovary, as compared with normal human ovary. These differentially expressed genes are involved in various biologic functions, such as cell division/apoptosis, regulation of gene expression and metabolism, reflecting the complexity of clinical manifestations of PCOS. The molecular characteristics established from our study will further our understanding of the pathogenesis of PCOS and help us to identify new targets for further studies and for the development of new therapeutic interventions.

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J H Li Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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F Sicard Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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M A Salam Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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M Baek Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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J LePrince Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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H Vaudry Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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K Kim Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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H B Kwon Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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J Y Seong Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Graduate School of Medicine, Korea University, Seoul 136-705, Korea

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Neurotensin (NT) is a tridecapeptide that functions as a neurotransmitter and neuromodulator in the nervous system. To date, three different types of NT receptor (NTR), NTR1, NTR2 and NTR3, have been identified only in mammalian species. In the present study we isolated the cDNAs for an NTR1 and a novel NTR in the bullfrog brain, designated bfNTR1 and bfNTR4 respectively. bfNTR1 and bfNTR4 encode 422- and 399-amino acid residue proteins respectively. bfNTR1 has a 64% amino acid identity with mammalian NTR1, and 34–37% identity with mammalian NTR2. bfNTR4 exhibits 43% and 45–47% identity with mammalian NTR1 and NTR2 respectively. Both receptors are mainly expressed in the brain and pituitary. bfNTR1 triggers both CRE-luc, a protein kinase A (PKA)-specific reporter, and c-fos-luc, a PKC-specific reporter, activities, indicating that bfNTR1 can activate PKA- and PKC-linked signaling pathways. However, bfNTR4 appears to be preferentially coupled to the PKA-linked pathway as it induces a higher CRE-luc activity than c-fos-luc activity. bfNTRs exhibit different pharmacological properties as compared with mammalian NTRs. Mammalian NTR1 but not NTR2 responds to NT, whereas both bfNTR1 and bfNTR4 show a high sensitivity to NT. SR 48692 and SR 142948A, antagonists for mammalian NTR1 but agonists for mammalian NTR2, function as antagonists for both bfNTR1 and bfNTR4. In conclusion, this report provides the first molecular, pharmacological and functional characterization of two NTRs in a non-mammalian vertebrate. These data should help to elucidate the phylogenetic history of the G protein-coupled NTRs in the vertebrate lineage as well as the structural features that determine their pharmacological properties.

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W M Liu State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing, People’s Republic of China 100080
Graduate School of the Chinese Academy of Sciences, 19 Yu-quan Road, Beijing, People’s Republic of China 100039

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Y J Cao State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing, People’s Republic of China 100080
Graduate School of the Chinese Academy of Sciences, 19 Yu-quan Road, Beijing, People’s Republic of China 100039

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Y J Yang State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing, People’s Republic of China 100080
Graduate School of the Chinese Academy of Sciences, 19 Yu-quan Road, Beijing, People’s Republic of China 100039

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J Li State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing, People’s Republic of China 100080
Graduate School of the Chinese Academy of Sciences, 19 Yu-quan Road, Beijing, People’s Republic of China 100039

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Z Hu State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing, People’s Republic of China 100080
Graduate School of the Chinese Academy of Sciences, 19 Yu-quan Road, Beijing, People’s Republic of China 100039

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E-K Duan State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing, People’s Republic of China 100080
Graduate School of the Chinese Academy of Sciences, 19 Yu-quan Road, Beijing, People’s Republic of China 100039

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The expression of tetraspanin CD9 was found on blastocysts in mice and endometrium epithelial cells in human and bovine. However, it remains unknown how CD9 is involved in the precise dialogue between embryo and uterus during early pregnancy. This study was designed to investigate the functional roles of CD9 in the embryo implantation with monoclonal antibody against CD9 protein (anti-CD9 mAb) and antisense oligonucleotide against CD9 gene (AS-CD9). Our results showed that intrauterine injection of anti-CD9 mAb on day 4 of pregnancy significantly increased the number of embryos implanted (7.24±0.39 versus 4.04±0.38). In vitro, anti-CD9 mAb or AS-CD9 significantly enhanced embryo-outgrowth ability on the monolayer of uterus epithelial cells in a dose-dependent manner. However, the attachment of blastocysts to epithelial cells was unaffected. Furthermore, we found that anti-CD9 mAb or AS-CD9 stimulated matrix metalloproteinase 2 (MMP-2) production of blastocysts on Fibronectin. LY294002, a specific inhibitor of phosphoinositide 3-kinase, was able to counteract the effect of anti-CD9 mAb and AS-CD9 on outgrowth ability and production of MMP-2. Our results indicated that CD9 played a role of inhibiting embryo implantation. CD9 was able to impair embryo invasion and the production of MMP-2 through the phosphoinositide 3-kinase signaling pathway.

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Iad Alhallak Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Keith G Wolter Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Ana Castro Munoz Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Frank A Simmen Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
The Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Richard J Ward Harding University, Searcy, Arkansas, USA

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Stacy A Petty Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Lin-Xi Li Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Rosalia C M Simmen Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
The Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

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Epidemiological studies inversely associate BMI with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the ‘local’ environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI = 27 kg/m2) and obese (mean BMI = 44 kg/m2) women. Breast adipose from obese women showed higher expression levels of adipogenic, pro-inflammatory, and estrogen synthetic genes than from non-obese women. Obese breast glandular tissue displayed lower proliferation and inflammatory status and higher expression of anti-proliferative/pro-senescence biomarkers TP53 and p21 than from non-obese women. Transcript levels for T-cell receptor and co-receptors CD3 and CD4 were higher in breast adipose of obese cohorts, coincident with elevated adipose interleukin 10 (IL10) and FOXP3 gene expression. In human breast epithelial cell lines MCF10A and HMEC, recombinant human IL10 reduced cell viability and CCND1 transcript levels, increased those of TP53 and p21, and promoted (MCF10A) apoptosis. Our findings suggest that breast adipose-associated IL10 may mediate paracrine interactions between non-diseased breast adipose and breast glandular compartments and highlight how breast adipose may program the local inflammatory milieu, partly by recruiting FOXP3+ T regulatory cells, to influence premenopausal breast cancer risk.

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