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S Y James
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A G Mackay
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K W Colston
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ABSTRACT

The effects of the novel vitamin D analogue, EB1089 alone, or in combination with the retinoid, 9-cis retinoic acid (9-cis RA) on indices of apoptosis in MCF-7 breast cancer cells have been examined. EB1089 was capable of reducing bcl-2 protein, a suppressor of apoptosis, and increasing p53 protein levels in MCF-7 cell cultures following 96h treatment. In the presence of 9-cis RA, EB1089 acted to further enhance the down-regulation and up-regulation of bcl-2 and p53 respectively.

Furthermore, EB1089 induces DNA fragmentation in MCF-7 cells, a key feature of apoptosis, alone and in combination with 9-cis RA in situ. The observation that EB1089 and 9-cis RA act in a cooperative manner to enhance induction of apoptosis in these cells may have therapeutic implications.

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Y-J Y Wan
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T Pan
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L Wang
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J Locker
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T-C J Wu
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In McA-RH 8994 rat hepatoma cells, all-transretinoic acid (t-RA) induces expression of the α-fetoprotein (AFP) and albumin genes and results in a phenotype similar to differentiated fetal hepatocytes. The present study elucidated the mechanism involved in AFP gene regulation mediated by retinoic acid. Northern blot analyses demonstrated that 9-cis-retinoic acid (c-RA), a ligand for retinoid x receptors (RXRs), also induced expression of the AFP gene in McA-RH 8994 cells. The induction was time- and dose-dependent. Northern blots and transfection assays using the 7·3 kb full-length regulatory region of the AFP gene demonstrated that c-RA was more effective than t-RA in regulating expression of the AFP gene. At 10−7m, c-RA increased AFP mRNA 5-fold and chloramphenicol acetyltransferase (CAT) activity 2·5-fold. In contrast, t-RA at a concentration of 10−7 m exerted no significant effect; 10− 6 to 10−5 m t-RA was needed to affect AFP gene expression. These data suggested that activation of RXRs is essential for the regulation of the AFP gene. Co-transfection experiments revealed that overexpression of RXRα in McA-RH 8994 cells further enhanced the CAT activity induced by c-RA. In addition, c-RA did not alter the half-life of AFP mRNA. Thus, RXRα may play a crucial role in transcriptional regulation of the AFP gene and in controlling hepatocyte phenotype.

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K Maehara
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T Hida
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Y Abe
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A Koga
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K Ota
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E Kutoh
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We undertook a study of molecular interference of nuclear orphan receptors. Nuclear receptor response element-1 (NRRE-1) from the human medium-chain acyl coenzyme A dehydrogenase (MCAD) gene promoter was shown to contain three hexamer elements (site 1 through 3) that are known to interact with a number of nuclear receptors including chicken ovalbumin upstream promoter transcription factor (COUP-TF) and estrogen-related receptor alpha (ERRalpha). We demonstrated that the peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha (PPARalpha/RXRalpha) heterodimer complex can also bind to the two hexamer repeat sequences (between site 1 and site 3) arranged as an everted imperfect repeat separated by 14 bp (ER14). Mutations of the putative core elements have shown that these three sites are differentially involved in ERRalpha and PPARalpha/RXRalpha binding. Homodimer of ERRalpha was shown to interact between site 1 and site 3 (ER14). To date, no nuclear receptor is known to bind to response elements over such long intervals. Interestingly, site 1 was shown to be essential for ERRalpha binding while site 3 supports its binding only in the presence of site 1. Furthermore, it was shown that the binding profile of ERRalpha and PPARalpha/RXRalpha are competitive rather than making a high order complex within NRRE-1. At the cellular level, transcriptional activation driven by the PPARalpha/RXRalpha complex was counteracted by the expression of ERRalpha in HeLa cells. These results suggest that ERRalpha and PPARalpha/RXRalpha could interfere with each other's function through binding to similar DNA elements, thereby finetuning the transcriptional outcome of the target gene. Our findings suggest a mechanism whereby multiple nuclear receptors can activate or repress DNA binding or transcription via a single pleiotropic regulatory element.

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D Bouton INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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H Escriva INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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R L de Mendonça INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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C Glineur INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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B Bertin INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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C Noël INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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M Robinson-Rechavi INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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A de Groot INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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J Cornette INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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V Laudet INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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R J Pierce INSERM U 547, Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
CNRS UMR 49, École Normale Supérieure de Lyon, 46 allée d’Italie, 69364-Lyon, France
INSERM U 545 Institut Pasteur, 1 rue du Professeur Calmette, 59019-Lille, France
Laboratoire d’Écologie Microbienne de la Rhizosphère (LEMiR), Département d’Écophysiologie Végétale et de Microbiologie (DEVM), CEA Cadarache, 13108 Saint Paul Lez Durance, France

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, Euromedex, Mundolsheim, France) under the conditions recommended by the supplier. The pTL1 plasmid was used as a carrier when necessary. Ligands (ethanol solution of 9 -cis retinoic acid 10 mM; ethanol solution of cis -4,7,10,13,16,19-docosahexanoic acid

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A Pestka
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B Toth Department of Obstetrics and Gynaecology–Innenstadt, Department of Obstetrics and Gynaecology, Ludwig‐Maximilians‐University Munich, Maistrasse 11, 80337 Munich, Germany

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C Kuhn
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S Hofmann
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I Wiest
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G Wypior
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K Friese
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U Jeschke
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vitamin A derivatives, so-called retinoids ( Singh et al . 2006 ). Retinoids are initially taken with food and via oxidation processes they are converted into retinoic acid, of which different isoforms such as 9- cis -retinoic acid (9- cis RA), 13- cis RA

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Maciej Pietrzak Department of Endocrinology, Department of Biochemistry and Molecular Biology, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland

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Monika Puzianowska-Kuznicka Department of Endocrinology, Department of Biochemistry and Molecular Biology, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland
Department of Endocrinology, Department of Biochemistry and Molecular Biology, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland

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, Onate et al . 1995 , McKenna et al . 1999 , Weiss & Ramos 2004 ), and with other proteins such as 9- cis -retinoic acid receptors (RXRs) ( Rastinjead 2001 , Szanto et al . 2004 ). The non-genomic mode of action of T 3 is more complex and, in some

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KW Colston
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CM Perks
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SP Xie
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JM Holly
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The effects of two vitamin D analogues, EB1089 and CB1093, on insulin-like growth factor binding protein (IGFBP) expression have been examined in MCF-7 and Hs578T human breast cancer cell lines. Both vitamin D analogues inhibited IGF-1 stimulated growth of MCF-7 cells and enhanced the production of IGFBP-3 as determined by Western-ligand blotting. Recombinant human IGFBP-3 inhibited the growth of MCF-7 cells over the concentration range 1-235 ng/ml. Hs578T cells were unresponsive to the mitogenic effects of IGF-1 but growth was inhibited by the two vitamin D analogues. Treatment of Hs578T cells with EB1089 and CB1093 (10 nM) as well as 100 nM 9-cis retinoic acid (9-cis RA) or all-trans retinoic acid (ATRA) was associated with increased accumulation of IGFBP-3 in conditioned medium. Furthermore, cotreatment of Hs578T cells with EB1089 and 9-cis RA led to augmented effects on both inhibition of cell growth and IGFBP-3 accumulation in conditioned medium as assessed by Western ligand blotting and radioimmunoassay. These findings suggest a role for IGFBP-3 in the growth inhibitory effects of vitamin D analogues.

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L Laflamme
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G Hamann
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N Messier
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S Maltais
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Langlois M-F
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Thyroid hormone receptors (TRs) often modulate transcriptional activity of target genes by heterodimerization with the 9-cis retinoic acid receptor (RXR). On positive thyroid response elements (TREs), RXR favors binding of the TR-RXR complex to DNA and stimulates transcription. RXR action on negative TREs is unclear. Furthermore, the single half-site configuration of many negative TREs does not favor the binding of a classic TR-RXR heterodimer. In a comparative study using CV-1 cells (relatively RXR- and TR-deficient) and JEG-3 cells (relatively TR-deficient), we demonstrate the importance of RXR in the negative transcriptional regulation of genes of the hypothalamo-pituitary axis by tri-iodothyronine. While RXR has variable effects on ligand-independent activation produced by TRs, it was required for efficient ligand-dependent repression of the TRH gene for TRalpha1 and TRbeta1 and of the TSH genes by all TRs. Using different RXR constructs we also observed the importance of the C-terminus of RXR but not of the N-terminus nor the DNA-binding domain, in the potentiation of negative regulation. We thus suggest that, with regard to negative regulation of the TRH and TSH genes by thyroid hormones, RXR behaves more like a cofactor than a classic heterodimerization partner.

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I Issemann
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R A Prince
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J D Tugwood
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S Green
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ABSTRACT

The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about tenfold in the livers of treated rodents. We have previously shown that a peroxisome proliferator response element (PPRE) is located 570 bp upstream of the rat peroxisomal acyl CoA oxidase gene and that PPAR binds to it. We show here that the retinoid X receptor (RXR) is required for PPAR to bind to the PPRE, and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. We have also shown that a variety of hypolipidaemic drugs and fatty acids can activate PPAR. This supports the suggestion that the physiological role of PPAR is to regulate fatty acid homeostasis, and provides further evidence that PPAR is the target of the fibrate class of hypolipidaemic drugs. Finally, we have demonstrated that a metabolically stabilized fatty acid is a potent PPAR activator, suggesting that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR.

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Jan Wilde Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, Nonnenplan 4,
07743 Jena, Germany

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Maria Erdmann Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, Nonnenplan 4,
07743 Jena, Germany

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Michael Mertens Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, Nonnenplan 4,
07743 Jena, Germany

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Gabriele Eiselt Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, Nonnenplan 4,
07743 Jena, Germany

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Martin Schmidt Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, Nonnenplan 4,
07743 Jena, Germany

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Estrogen synthesis in adipose tissue is associated with the development of breast cancer. Tumors are preferentially found in breast quadrants with strongest expression of the cytochrome P450 aromatase (encoded by the gene CYP19A1). Several promoters regulated by various hormonal factors drive aromatase expression in human breast adipose fibroblasts (BAFs). As adipose tissue is a major source of retinoids, in this study, we investigated their role in the regulation of aromatase expression. The retinoids all-trans-retinoic acid (at-RA) and 9-cis-RA induce aromatase activity in human BAFs. In BAFs, at-RA induces aromatase gene expression via promoter I.4. In 3T3-L1 cells, both retinoids specifically drive luciferase reporter gene expression under the control of aromatase promoter I.4, whereas other promoters active in human adipose tissue are insensitive. Activation by retinoids depends on a 467 bp fragment (−256/+211) of promoter I.4 containing four putative retinoic acid response elements (RAREs). Site-directed mutagenesis revealed that only RARE2 (+91/+105) mediates the retinoid-dependent induction of reporter gene activity. In 3T3-L1 preadipocytes and human BAFs, RA receptor α (RARα (RARA)) expression is predominant, whereas RARβ (RARB) or RARγ (RARG) expression is low. Electrophoretic mobility shift assays with nuclear extracts obtained from human BAFs and 3T3-L1 cells identified a specific RARE2-binding complex. Retinoids enhanced complex formation, whereas pre-incubation with anti-RARα antibodies prohibited the binding of RARα to RARE2. Chromatin immunoprecipitation showed RA-dependent binding of RARα to the RARE2-containing promoter region in vivo. Furthermore, we provide evidence that RARE2 is also necessary for the basal activation of promoter I.4 in these cells. Taken together, these findings indicate a novel retinoid-dependent mechanism of aromatase activity induction in adipose tissue.

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