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F Wang
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R Duan
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J Chirgwin
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SH Safe
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Insulin-like growth factor-I (IGF-I), transforming growth factor alpha (TGFalpha) and epidermal growth factor (EGF) induced cathepsin D gene expression and reporter gene activity in MCF-7 human breast cancer cells transiently transfected with a construct (pCD1) containing a -2576 to -124 cathepsin D gene promoter insert. In contrast, IGF-I, but not TGFalpha or EGF, induced reporter gene activity in cells cotransfected with wild-type estrogen receptor (ER) expression plasmid and a construct (pCD2) containing estrogen-responsive downstream elements from -208 to -101. Promoter deletion and mutational analysis experiments identified four GC-rich sites and an imperfect palindromic estrogen responsive element required for IGF-I activation of the ER (ligand-independent). Subsequent studies with the mitogen-activated protein kinase (MAPK) inhibitor, PD98059, and a serine(118(-ER mutant confirmed the role of the MAPK pathway for IGF-I activation of the ER in MCF-7 cells. Thus, growth factor activation of ER can mediate transactivation vs ER/Sp1 binding to GC-rich sites and represents a novel pathway for ligand-independent ER action. The divergent pathways for IGF-I and TGFalpha/EGF activation of the ER observed in MCF-7 cells contrast with previous data indicating that pathways for growth factor activation of the ER are dependent on the gene and/or gene promoter and on cell context.

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W Porter
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F Wang
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R Duan
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C Qin
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E Castro-Rivera
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K Kim
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S Safe
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Heat shock protein 27 (Hsp 27) is expressed in mammary tumors and may play a role in tumor growth and response to anti-neoplastic drug therapy. 17beta-Estradiol (E2) induces Hsp 27 mRNA levels in MCF-7 human breast cancer cells, and we have investigated the comparative inhibitory mechanisms using the aryl hydrocarbon receptor (AhR) agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the direct-acting antiestrogen ICI 164,384. TCDD inhibited E2-induced Hsp 27 gene expression and analysis of the Hsp 27 gene promoter showed that the inhibitory response was associated with AhR interactions with a pentanucleotide motif at -3 to +2 in the promoter that corresponded to the core sequence of a dioxin responsive element. In contrast, ICI 164,384 induced Hsp 27 gene expression and reporter gene activity in MCF-7 cells and this represents one of the few examples of the estrogen receptor-alpha (ERalpha) agonist activity of the 'pure' antiestrogen ICI 164,384.

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M Zhang Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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Y Tao Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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B Zhou Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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H Xie Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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F Wang Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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L Lei Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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L Huo Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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Q Sun Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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G Xia Department of Animal Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, People’s Republic of China
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China

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Atrial natriuretic peptide (ANP) as well as its receptors is found in mammalian ovary and follicular cells and its function in oocyte meiotic maturation has also been reported in Xenopus, hamster and rat. But the results are controversial and the physiological mechanism of ANP on oocyte maturation is not clear, especially the relationship between gonadotrophin and ANP as well as the signal transduction, and these need further study. The present study conducted experiments to examine these questions by using drug treatment and Western blot analysis and focused on pig oocyte meiotic maturation and cumulus expansion in vitro. The results revealed that ANP could inhibited FSH-induced pig oocyte maturation and cumulus expansion and prevent the full phosphorylation of mitogen-activated protein kinase in both oocytes and cumulus cells, and that these inhibitory effects could be mimicked by 8-Br-cyclic guanosine 5′-monophosphate (8-Br-cGMP), but blocked by a protein kinase G (PKG) inhibitor KT5823. Zaprinast, a cGMP-specific phosphodiesterase inhibitor, could enhance the inhibitory effect of ANP on oocyte maturation. A specific analogue of ANP, C-ANP-(4–23), which binds to the natriuretic peptide receptor-C (NPRC), had no effect in either FSH-induced or spontaneous oocyte maturation. Treatment with forskolin, a stimulator of adenylate cyclase, had a biphasic effect; 44 h treatment induced cumulus expansion but inhibited oocyte maturation while 2 h treatment induced maturation of cumulus-enclosed oocytes (CEOs). Both ANP and C-ANP-(4–23) could inhibit the effect of forskolin on CEO maturation, and these inhibitory effects of ANP/C-ANP-(4–23) could be blocked by preincubation with pertussis toxin (PT), consistent with mediation by a Gi protein(s) in the cumulus cells. All these results suggest that ANP is a multifunctional regulator of FSH and forskolin on pig CEO maturation by two signalling mechanisms: one is via a cGMP/PKG pathway, the other is via NPRC receptors in cumulus cells and the activation of the PT-sensitive Gi protein(s).

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J A Hansen
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L H Hansen
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X Wang
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J J Kopchick
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F Gouilleux
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B Groner
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J H Nielsen
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A Møldrup
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E D Galsgaard
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N Billestrup
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ABSTRACT

Stimulation of GH receptors leads to rapid activation of Jak2 kinase and subsequent tyrosine phosphorylation of the GH receptor. Three specific tyrosines located in the C-terminal domain of the GH receptor have been identified as being involved in GH-stimulated transcription of the Spi 2·1 promoter. Mutated GH receptors lacking all but one of these three tyrosines are able to mediate a transcriptional response when transiently transfected into CHO cells together with a Spi 2·1 promoter/luciferase construct. Similarly, these GH receptors were found to be able to mediate activation of Stat5 DNA-binding activity, whereas the GH receptor mutant lacking all intracellular tyrosines was not. Synthetic tyrosine phosphorylated peptides corresponding to the GH receptor sequence around the three tyrosines inhibited Stat5 DNA-binding activity while their non-phosphorylated counterparts were ineffective. Tyrosine phosphorylated GST-GH receptor fusion proteins specifically bound to Stat5 in extracts from COS 7 cells transfected with Stat5 cDNA. This binding could be inhibited by tyrosine phosphorylated peptides derived from the GH receptor. This study thus demonstrated that specific GH receptor tyrosine residues, in their phosphorylated state, are involved in transcriptional signaling by directly interacting with Stat5.

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Z Ma Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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D F J Ketelhuth Department of Medicine, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

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T Wirström Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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T Ohki Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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M J Forteza Department of Medicine, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

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H Wang Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland

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V Grill Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Institute of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

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C B Wollheim Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland

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A Björklund Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Modified lipoproteins can negatively affect beta cell function and survival. However, the mechanisms behind interactions of modified lipoproteins with beta cells – and in particular, relationships to increased uptake – are only partly clarified. By over-expressing the scavenger receptor CD36 (Tet-on), we increased the uptake of fluorescent low-density modified lipoprotein (oxLDL) into insulin-secreting INS-1 cells. The magnitude of uptake followed the degree of CD36 over-expression. CD36 over-expression increased concomitant efflux of 3H-cholesterol in proportion to the cellular contents of 3H-cholesterol. Exposure to concentrations of oxLDL from 20 to 100 µg/mL dose-dependently increased toxicity (evaluated by MTT) as well as apoptosis. However, the increased uptake of oxLDL due to CD36 over-expression did not exert additive effects on oxLDL toxicity – neither on viability, nor on glucose-induced insulin release and cellular content. Reciprocally, blocking CD36 receptors by Sulfo-N-Succinimidyl Oleate decreased the uptake of oxLDL but did not diminish the toxicity. Pancreatic islets of CD36−/− mice displayed reduced uptake of 3H-cholesterol-labeled oxLDL vs wild type but similar toxicity to oxLDL. OxLDL was found to increase the expression of CD36 in islets and INS-1 cells. In summary, given the experimental conditions, our results indicate that (1) increased uptake of oxLDL is not responsible for toxicity of oxLDL, (2) increased efflux of the cholesterol moiety of oxLDL counterbalances, at least in part, increased uptake and (3) oxLDL participates in the regulation of CD36 in pancreatic islets and in INS-1 cells.

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