7 results on '"G. Meduri"'
Search Results
2. Osmotic Stress and MR Expression
- Author
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Say Viengchareun, Peter Kamenicky, Nicolas Blanchard-Gutton, Aurélie Lanel, Marcel Blot-Chabaud, Nadia Cherradi, Shoshana Sztal-Mazer, Laetitia Martinerie, G. Meduri, Marie Teixeira, Marc Lombès, Daniel Butlen, Evelyne Ferrary, Christine Kurschat, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Chirurgie otologique mini-invasive robotisée, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique moléculaire, pharmacogénétique et hormonologie, Physiopathologie de l'Endothelium, Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Angiogenèse hormono-regulée et angiogenèse tumorale (LAPV), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM) more...
- Subjects
Epithelial sodium channel ,Male ,Osmosis ,Hypertonic Solutions ,Electrophoretic Mobility Shift Assay ,030204 cardiovascular system & hematology ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Endocrinology ,Mineralocorticoid receptor ,MESH: Receptors, Mineralocorticoid ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,Enhancer binding ,MESH: Sodium ,MESH: Animals ,Aldosterone ,Original Research ,Regulation of gene expression ,0303 health sciences ,Protein Stability ,Reverse Transcriptase Polymerase Chain Reaction ,General Medicine ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,MESH: Gene Expression Regulation ,Immunohistochemistry ,Targeted Oncogenesis ,Hypotonic Solutions ,MESH: Hypotonic Solutions ,MESH: Mice, Transgenic ,medicine.drug_class ,Blotting, Western ,Mice, Transgenic ,Biology ,Transfection ,Mineralocorticoid Receptor ,Cell Line ,03 medical and health sciences ,MESH: Protein Stability ,medicine ,MESH: Blotting, Western ,Animals ,Kidney Tubules, Collecting ,Enhancer ,Renal Cell Line ,MESH: Kidney Tubules, Collecting ,MESH: Mice ,Molecular Biology ,Transcription factor ,030304 developmental biology ,MESH: Osmosis ,Ion Transport ,MESH: Transfection ,Tis11b ,Sodium ,MESH: Aldosterone ,MESH: Immunohistochemistry ,Molecular biology ,MESH: Male ,MESH: Cell Line ,MESH: Ion Transport ,Receptors, Mineralocorticoid ,chemistry ,Gene Expression Regulation ,TonEBP ,Mineralocorticoid ,MESH: Electrophoretic Mobility Shift Assay ,MESH: Hypertonic Solutions - Abstract
International audience; Aldosterone effects are mediated by the mineralocorticoid receptor (MR), a transcription factor highly expressed in the distal nephron. Given that MR expression level constitutes a key element controlling hormone responsiveness, there is much interest in elucidating the molecular mechanisms governing MR expression. To investigate whether hyper- or hypotonicity could affect MR abundance, we established by targeted oncogenesis a novel immortalized cortical collecting duct (CCD) cell line and examined the impact of osmotic stress on MR expression. KC3AC1 cells form domes, exhibit a high transepithelial resistance, express 11beta-hydroxysteroid dehydrogenase 2 and functional endogenous MR, which mediates aldosterone-stimulated Na(+) reabsorption through the epithelial sodium channel activation. MR expression is tightly regulated by osmotic stress. Hypertonic conditions induce expression of tonicity-responsive enhancer binding protein, an osmoregulatory transcription factor capable of binding tonicity-responsive enhancer response elements located in MR regulatory sequences. Surprisingly, hypertonicity leads to a severe reduction in MR transcript and protein levels. This is accompanied by a concomitant tonicity-induced expression of Tis11b, a mRNA-destabilizing protein that, by binding to the AU-rich sequences of the 3'-untranslated region of MR mRNA, may favor hypertonicity-dependent degradation of labile MR transcripts. In sharp contrast, hypotonicity causes a strong increase in MR transcript and protein levels. Collectively, we demonstrate for the first time that optimal adaptation of CCD cells to changes in extracellular fluid composition is accompanied by drastic modification in MR abundance via transcriptional and posttranscriptional mechanisms. Osmotic stress-regulated MR expression may represent an important molecular determinant for cell-specific MR action, most notably in renal failure, hypertension, or mineralocorticoid resistance. more...
- Published
- 2009
- Full Text
- View/download PDF
Catalog
3. A new strategy for selective targeting of progesterone receptor with passive antagonists.
- Author
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Khan JA, Tikad A, Fay M, Hamze A, Fagart J, Chabbert-Buffet N, Meduri G, Amazit L, Brion JD, Alami M, Lombès M, Loosfelt H, and Rafestin-Oblin ME
- Subjects
- Active Transport, Cell Nucleus, Androstenes, Binding Sites, Cell Line, Tumor drug effects, Drug Screening Assays, Antitumor, Female, HEK293 Cells, Homosteroids chemical synthesis, Humans, Models, Molecular, Protein Binding, Proteolysis drug effects, Receptors, Progesterone agonists, Receptors, Progesterone metabolism, Steroids chemical synthesis, Transcription Factors metabolism, Antineoplastic Agents, Hormonal pharmacology, Breast Neoplasms drug therapy, Homosteroids pharmacology, Neoplasms, Hormone-Dependent drug therapy, Receptors, Progesterone antagonists & inhibitors, Steroids pharmacology
- Abstract
Currently available progesterone (P4) receptor (PR) antagonists, such as mifepristone (RU486), lack specificity and display partial agonist properties, leading to potential drawbacks in their clinical use. Recent x-ray crystallographic studies have identified key contacts involved in the binding of agonists and antagonists with PR opening the way for a new rational strategy for inactivating PR. We report here the synthesis and characterization of a novel class of PR antagonists (APRn) designed from such studies. The lead molecule, the homosteroid APR19, displays in vivo endometrial anti-P4 activity. APR19 inhibits P4-induced PR recruitment and transactivation from synthetic and endogenous gene promoters. Importantly, it exhibits high PR selectivity with respect to other steroid hormone receptors and is devoid of any partial agonist activity on PR target gene transcription. Two-hybrid and immunostaining experiments reveal that APR19-bound PR is unable to interact with either steroid receptor coactivators 1 and 2 (SRC1 and SCR2) or nuclear receptor corepressor (NcoR) and silencing mediator of retinoid acid and thyroid hormone receptor (SMRT), in contrast to RU486-PR complexes. APR19 also inhibits agonist-induced phosphorylation of serine 294 regulating PR transcriptional activity and turnover kinetics. In silico docking studies based on the crystal structure of the PR ligand-binding domain show that, in contrast to P4, APR19 does not establish stabilizing hydrogen bonds with the ligand-binding cavity, resulting in an unstable ligand-receptor complex. Altogether, these properties highly distinguish APR19 from RU486 and likely its derivatives, suggesting that it belongs to a new class of pure antiprogestins that inactivate PR by a passive mechanism. These specific PR antagonists open new perspectives for long-term hormonal therapy. more...
- Published
- 2013
- Full Text
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4. Osmotic stress regulates mineralocorticoid receptor expression in a novel aldosterone-sensitive cortical collecting duct cell line.
- Author
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Viengchareun S, Kamenicky P, Teixeira M, Butlen D, Meduri G, Blanchard-Gutton N, Kurschat C, Lanel A, Martinerie L, Sztal-Mazer S, Blot-Chabaud M, Ferrary E, Cherradi N, and Lombès M
- Subjects
- Animals, Blotting, Western, Cell Line, Electrophoretic Mobility Shift Assay, Gene Expression Regulation drug effects, Hypertonic Solutions pharmacology, Hypotonic Solutions pharmacology, Immunohistochemistry, Ion Transport drug effects, Kidney Tubules, Collecting cytology, Male, Mice, Mice, Transgenic, Protein Stability, Receptors, Mineralocorticoid genetics, Reverse Transcriptase Polymerase Chain Reaction, Sodium metabolism, Transfection, Aldosterone pharmacology, Osmosis drug effects, Osmosis physiology, Receptors, Mineralocorticoid metabolism
- Abstract
Aldosterone effects are mediated by the mineralocorticoid receptor (MR), a transcription factor highly expressed in the distal nephron. Given that MR expression level constitutes a key element controlling hormone responsiveness, there is much interest in elucidating the molecular mechanisms governing MR expression. To investigate whether hyper- or hypotonicity could affect MR abundance, we established by targeted oncogenesis a novel immortalized cortical collecting duct (CCD) cell line and examined the impact of osmotic stress on MR expression. KC3AC1 cells form domes, exhibit a high transepithelial resistance, express 11beta-hydroxysteroid dehydrogenase 2 and functional endogenous MR, which mediates aldosterone-stimulated Na(+) reabsorption through the epithelial sodium channel activation. MR expression is tightly regulated by osmotic stress. Hypertonic conditions induce expression of tonicity-responsive enhancer binding protein, an osmoregulatory transcription factor capable of binding tonicity-responsive enhancer response elements located in MR regulatory sequences. Surprisingly, hypertonicity leads to a severe reduction in MR transcript and protein levels. This is accompanied by a concomitant tonicity-induced expression of Tis11b, a mRNA-destabilizing protein that, by binding to the AU-rich sequences of the 3'-untranslated region of MR mRNA, may favor hypertonicity-dependent degradation of labile MR transcripts. In sharp contrast, hypotonicity causes a strong increase in MR transcript and protein levels. Collectively, we demonstrate for the first time that optimal adaptation of CCD cells to changes in extracellular fluid composition is accompanied by drastic modification in MR abundance via transcriptional and posttranscriptional mechanisms. Osmotic stress-regulated MR expression may represent an important molecular determinant for cell-specific MR action, most notably in renal failure, hypertension, or mineralocorticoid resistance. more...
- Published
- 2009
- Full Text
- View/download PDF
5. Ligand-controlled interaction of histone acetyltransferase binding to ORC-1 (HBO1) with the N-terminal transactivating domain of progesterone receptor induces steroid receptor coactivator 1-dependent coactivation of transcription.
- Author
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Georgiakaki M, Chabbert-Buffet N, Dasen B, Meduri G, Wenk S, Rajhi L, Amazit L, Chauchereau A, Burger CW, Blok LJ, Milgrom E, Lombès M, Guiochon-Mantel A, and Loosfelt H
- Subjects
- Animals, Cell Line, Chlorocebus aethiops, Hormones metabolism, Humans, Ligands, Nuclear Receptor Coactivator 1, Origin Recognition Complex genetics, Protein Binding, Protein Subunits genetics, Protein Subunits metabolism, Receptors, Progesterone genetics, Receptors, Steroid metabolism, Signal Transduction, Transcription Factors, Histone Acetyltransferases metabolism, Origin Recognition Complex metabolism, Receptors, Progesterone metabolism, Transcription, Genetic genetics, Transcriptional Activation genetics
- Abstract
Modulators of cofactor recruitment by nuclear receptors are expected to play an important role in the coordination of hormone-induced transactivation processes. To identify such factors interacting with the N-terminal domain (NTD) of the progesterone receptor (PR), we used this domain as bait in the yeast Sos-Ras two-hybrid system. cDNAs encoding the C-terminal MYST (MOZ-Ybf2/Sas3-Sas2-Tip60 acetyltransferases) domain of HBO1 [histone acetyltransferase binding to the origin recognition complex (ORC) 1 subunit], a member of the MYST acetylase family, were thus selected from a human testis cDNA library. In transiently transfected CV1 cells, the wild-type HBO1 [611 amino acids (aa)] enhanced transcription mediated by steroid receptors, notably PR, mineralocorticoid receptor, and glucocorticoid receptor, and strongly induced PR and estrogen receptor coactivation by steroid receptor coactivator 1a (SRC-1a). As assessed by two-hybrid and glutathione-S-transferase pull-down assays, the HBO1 MYST acetylase domain (aa 340-611) interacts mainly with the NTD, and also contacts the DNA-binding domain and the hinge domains of hormone-bound PR. The HBO1 N-terminal region (aa 1-340) associates additionally with PR ligand-binding domain (LBD). HBO1 was found also to interact through its NTD with SRC-1a in the absence of steroid receptor. The latter coassociation enhanced specifically activation function 2 activation function encompassed in the LBD. Conversely, the MYST acetylase domain specifically enhanced SRC-1 coupling with PR NTD, through a hormone-dependent mechanism. In human embryonic kidney 293 cells expressing human PRA or PRB, HBO1 raised selectively an SRC-1-dependent response of PRB but failed to regulate PRA activity. We show that HBO1 acts through modification of an LBD-controlled structure present in the N terminus of PRB leading to the modulation of SRC-1 functional coupling with activation function 3-mediated transcription. Importantly, real-time RT-PCR analysis also revealed that HBO1 enhanced SRC-1 coactivation of PR-dependent transcription of human endogenous genes such as alpha-6 integrin and 11beta-hydroxydehydrogenase 2 but not that of amphiregulin. Immunofluorescence and confocal microscopy of human embryonic kidney-PRB cells demonstrated that the hormone induces the colocalization of HBO1 with PR-SRC-1 complex into nuclear speckles characteristic of PR-mediated chromatin remodeling. Our results suggest that HBO1 might play an important physiological role in human PR signaling. more...
- Published
- 2006
- Full Text
- View/download PDF
6. The elongation factor ELL (eleven-nineteen lysine-rich leukemia) is a selective coregulator for steroid receptor functions.
- Author
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Pascual-Le Tallec L, Simone F, Viengchareun S, Meduri G, Thirman MJ, and Lombès M
- Subjects
- Animals, COS Cells, Chlorocebus aethiops, DNA-Binding Proteins genetics, Gene Expression Regulation physiology, Histone-Lysine N-Methyltransferase, Humans, Immunohistochemistry, Mutation, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins genetics, Peptide Elongation Factors genetics, Proto-Oncogenes genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Transcription Factors genetics, Transcription, Genetic physiology, Transcriptional Elongation Factors, DNA-Binding Proteins metabolism, Neoplasm Proteins metabolism, Peptide Elongation Factors metabolism, Receptors, Mineralocorticoid metabolism, Transcription Factors metabolism
- Abstract
The dynamic and coordinated recruitment of coregulators by steroid receptors is critical for specific gene transcriptional activation. To identify new cofactors of the human (h) mineralocorticoid receptor (MR), its highly specific N-terminal domain was used as bait in a yeast two-hybrid approach. We isolated ELL (eleven-nineteen lysine-rich leukemia), a RNA polymerase II elongation factor which, when fused to MLL (mixed lineage leukemia) contributes to the pathogenesis of acute leukemia. Specific interaction between hMR and ELL was confirmed by glutathione-S-transferase pull-down and coimmunoprecipitation experiments. Transient transfections demonstrated that ELL increased receptor transcriptional potency and hormonal efficacy, indicating that ELL behaves as a bona fide MR coactivator. Of major interest, ELL differentially modulates steroid receptor responses, with striking opposite effects on hMR and glucocorticoid receptor-mediated transactivation, without affecting that of androgen and progesterone receptors. Furthermore, the MLL-ELL fusion protein, as well as several ELL truncated mutants and the ELL L214V mutant, lost their ability to potentiate MR transcriptional activities, suggesting that both the elongation domain and the ELL-associated factor 1 interaction domains are required for ELL to fulfill its selector activity on steroid receptors. This study is the first direct demonstration of a functional interaction between a nuclear receptor and an elongation factor. These results provide further evidence that the selectivity of the mineralo vs. glucocorticoid signaling pathways also occurs at the transcriptional complex level and may have major pathophysiological implications, most notably in leukemogenesis and corticosteroid-induced apoptosis. These findings allow us to propose the concept of "transcriptional selector" for ELL on steroid receptor transcriptional functions. more...
- Published
- 2005
- Full Text
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7. New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype.
- Author
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Touraine P, Beau I, Gougeon A, Meduri G, Desroches A, Pichard C, Detoeuf M, Paniel B, Prieur M, Zorn JR, Milgrom E, Kuttenn F, and Misrahi M
- Subjects
- Adenylyl Cyclases drug effects, Adenylyl Cyclases metabolism, Adult, Amenorrhea drug therapy, Animals, COS Cells drug effects, COS Cells metabolism, Female, Follicle Stimulating Hormone pharmacology, Follicle Stimulating Hormone therapeutic use, Gene Silencing, Humans, Immunohistochemistry, Male, Ovary diagnostic imaging, Ovary pathology, Phenotype, Primary Ovarian Insufficiency drug therapy, Primary Ovarian Insufficiency genetics, Protein Processing, Post-Translational, Receptors, FSH drug effects, Receptors, FSH metabolism, Recombinant Proteins genetics, Recombinant Proteins metabolism, Sequence Analysis, Ultrasonography, Amenorrhea genetics, Mutation, Ovary physiopathology, Receptors, FSH genetics
- Abstract
Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12+/-3% residual activity, whereas in patient 1 a 24+/-4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient. more...
- Published
- 1999
- Full Text
- View/download PDF
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