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21 results on '"Jean-Christophe Pointud"'

1. Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice

Author: Damien Dufour, Typhanie Dumontet, Isabelle Sahut-Barnola, Aude Carusi, Méline Onzon, Eric Pussard, James Jr Wilmouth, Julie Olabe, Cécily Lucas, Adrien Levasseur, Christelle Damon-Soubeyrand, Jean-Christophe Pointud, Florence Roucher-Boulez, Igor Tauveron, Guillaume Bossis, Edward T. Yeh, David T. Breault, Pierre Val, Anne-Marie Lefrançois-Martinez, and Antoine Martinez
Subjects: Science
Abstract: SUMOylation is a mechanism of posttranslational modification involved in eukaryotic cell homeostasis. Here the authors report that mice unable to control SUMOylation in the adrenal cortex develop a selective defect in glucocorticoid production due to disrupted differentiation of cells involved in steroid hormone synthesis.
Published: 2022
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2. PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development

Author: Coralie Drelon, Annabel Berthon, Isabelle Sahut-Barnola, Mickaël Mathieu, Typhanie Dumontet, Stéphanie Rodriguez, Marie Batisse-Lignier, Houda Tabbal, Igor Tauveron, Anne-Marie Lefrançois-Martinez, Jean-Christophe Pointud, Celso E. Gomez-Sanchez, Seppo Vainio, Jingdong Shan, Sonia Sacco, Andreas Schedl, Constantine A. Stratakis, Antoine Martinez, and Pierre Val
Subjects: Science
Abstract: The adrenal cortex undergoes functional zonation to generate an outer zona glomerulosa (ZG) and inner zona fasciculata (ZF), but how this is regulated at a molecular level is unclear. Here, the authors show that ZG differentiation is stimulated by WNT signalling and that PKA blocks WNT signalling to allow ZF differentiation and also prevents WNT-induced cancer development.
Published: 2016
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3. Aldo-keto reductases 1B in adrenal cortex physiology

Author: Emilie PASTEL, Jean-Christophe Pointud, Antoine Martinez, and A-Marie Lefrançois Martinez
Subjects: Adrenal Cortex, Oxidative Stress, Prostaglandins F, ACTH, aldose reductase, mouse models, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Aldose reductase proteins are cytosolic monomeric enzymes, belonging to the aldo-keto reductase (AKR) superfamily. They perform oxidoreduction of carbonyl groups from a wide variety of substrates such as aliphatic and aromatic aldehydes or ketones. The Aldose reductase subgroup (AKR1B) is one of the most characterized because of its involvement in human diseases such as diabetic complications resulting from the ability of its human archetype AKR1B1 to reduce glucose into sorbitol. However the issue of AKR1B function in non pathologic condition remains poorly resolved. Adrenal steroidogenesis is strongly associated with high production of endogenous harmful lipid aldehyde by-products including isocaproaldehyde (4-methylpentanal) derived from cholesterol side chain cleavage (the first step of steroid synthesis) and 4-hydroxynonenal (4- HNE) that can both be reduced by AKR1B proteins. More recently, some AKR1B isoforms have been shown to be endowed with prostaglandin F synthase activity, suggesting that in addition to possible scavenger function, they could instigate paracrine signals. Interestingly, previous studies have established that the adrenal gland is one of the major site for human and murine AKR1B expression suggesting that their detoxifying/signaling activity could be specifically required for the correct handling of adrenal function. Moreover chronic effects of ACTH result in a coordinated regulation of genes encoding the steroidogenic enzymes and some AKR1B isoforms.This review presents the molecular mechanisms accounting for the adrenal specific expression of some AKR1B genes. Using data from recent mouse genetic models, we will try to connect their enzymatic properties and regulation with adrenal functions.
Published: 2016
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4. Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice.

Author: Isabelle Sahut-Barnola, Cyrille de Joussineau, Pierre Val, Sarah Lambert-Langlais, Christelle Damon, Anne-Marie Lefrançois-Martinez, Jean-Christophe Pointud, Geoffroy Marceau, Vincent Sapin, Frédérique Tissier, Bruno Ragazzon, Jérôme Bertherat, Lawrence S Kirschner, Constantine A Stratakis, and Antoine Martinez
Subjects: Genetics, QH426-470
Abstract: Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 alpha-regulatory subunit (R1alpha) of the cAMP-dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1alpha loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1alpha loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1alpha is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.
Published: 2010
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5. Aldo keto reductase 1B7 and prostaglandin F2alpha are regulators of adrenal endocrine functions.

Author: Sarah Lambert-Langlais, Jean-Christophe Pointud, Anne-Marie Lefrançois-Martinez, Fanny Volat, Michèle Manin, François Coudoré, Pierre Val, Isabelle Sahut-Barnola, Bruno Ragazzon, Estelle Louiset, Catherine Delarue, Hervé Lefebvre, Yoshihiro Urade, and Antoine Martinez
Subjects: Medicine, Science
Abstract: Prostaglandin F(2alpha) (PGF(2alpha)), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF(2alpha) synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF(2alpha) biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF(2alpha) but expressed different biosynthetic isozymes. In chromaffin cells, PGF(2alpha) secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF(2alpha) secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF(2alpha) release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF(2alpha) receptor was only detected in chromaffin cells, making medulla the primary target of PGF(2alpha) action. By comparing PGF(2alpha)-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF(2alpha) repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF(2alpha) may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal.
Published: 2009
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6. Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

Author: James J. Wilmouth, Julie Olabe, Diana Garcia-Garcia, Cécily Lucas, Rachel Guiton, Florence Roucher-Boulez, Damien Dufour, Christelle Damon-Soubeyrand, Isabelle Sahut-Barnola, Jean-Christophe Pointud, Yoan Renaud, Adrien Levasseur, Igor Tauveron, Anne-Marie Lefrançois-Martinez, Antoine Martinez, Pierre Val, Génétique, Reproduction et Développement (GReD), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)
Subjects: Male, Multidisciplinary, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Adrenal Cortex Neoplasms, Mice, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Adrenocortical Carcinoma, Androgens, Animals, Female
Abstract: SummaryIn contrast with most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Homozygous deletion of the negative WNT pathway regulator ZNRF3 is the most frequent alteration in ACC patients. Here, we show that Cre-mediated inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Indeed, although most knockout female mice develop metastatic carcinomas over an 18 month-time course, adrenal hyperplasia gradually regresses in male knockout mice. This male-specific regression is associated with induction of senescence and recruitment of macrophages, which differentiate as active phagocytes that clear-out senescent preneoplastic cells. Macrophage recruitment is also observed in female mice. However, it is delayed and dampened compared to males, which allows for tumour progression. Interestingly, testosterone treatment of female knockouts is sufficient to induce senescence, recruitment of phagocytic macrophages and regression of hyperplasia. We further show that although macrophages are present within adrenal tumours at 18 months, MERTKhigh active phagocytes are mostly found in indolent lesions in males but not in aggressive tumours in females. Consistent with our observations in mice, analysis of RNA sequencing data from the TCGA cohort of ACC shows that phagocytic macrophages are more prominent in men than women and associated with better prognosis. Altogether, these data establish that phagocytic macrophages prevent aggressive ACC development in male mice and suggest that they may play a key role in the unusual sexual dimorphism of ACC in patients.
Published: 2022
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7. Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

Author: Anne-Marie Lefrançois-Martinez, Amandine Septier, Amanda Swain, Jean-Christophe Pointud, Constantine A. Stratakis, Fabio R. Faucz, Florian Guillou, James Wilmouth, Antoine-Guy Lopez, Adrien Levasseur, Ingrid Plotton, Cyril Djari, Seppo Vainio, Crystal Kamilaris, Isabelle Sahut-Barnola, Hervé Lefebvre, Damien Dufour, Pierre Val, Nathanaëlle Montanier, Antoine Martinez, Igor Tauveron, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Hospices Civils de Lyon (HCL), CHU Clermont-Ferrand, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The institute of cancer research [London], and University of Oulu
Subjects: Male, Somatic cell, [SDV]Life Sciences [q-bio], Apoptosis, Mice, 0302 clinical medicine, Wnt4 Protein, Testis, WNT4, Genes, Tumor Suppressor, PRKAR1A, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Mice, Knockout, 0303 health sciences, Pigmentation, General Medicine, Seminiferous Tubules, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Sertoli cell, Phenotype, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Research Article, Cell type, Stromal cell, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Paracrine signalling, Testicular Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Paracrine Communication, medicine, Animals, Humans, Carney Complex, Carney complex, 030304 developmental biology, Sertoli Cells, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Cyclic AMP-Dependent Protein Kinases, Disease Models, Animal, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutation, Cancer research, Transcriptome
Abstract: International audience; Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.
Published: 2021
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8. EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness

Author: Bruno Ragazzon, Jean-Christophe Pointud, Houda Tabbal, Pierre Val, Igor Tauveron, Coralie Drelon, M. Batisse-Lignier, Cyril Djari, Stéphanie Rodriguez, Anne-Marie Lefrançois-Martinez, Amandine Septier, Jérôme Bertherat, Guillaume Assié, Isabelle Sahut-Barnola, Mickael Mathieu, Antoine Martinez, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Clermont-Ferrand, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Cancer Research, Adenosine, Indoles, Cell Cycle Proteins, MESH: Adrenal Cortex Neoplasms, MESH: Mice, Knockout, MESH: Proportional Hazards Models, MESH: Adrenocortical Carcinoma, 0302 clinical medicine, Gene expression, Adrenocortical Carcinoma, E2F1, MESH: Animals, Mice, Knockout, MESH: Chromatin Immunoprecipitation, MESH: Indoles, Regulation of gene expression, biology, EZH2, MESH: Gene Expression Regulation, Neoplastic, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Ribonucleoside Diphosphate Reductase, 3. Good health, Gene Expression Regulation, Neoplastic, Securin, MESH: E2F1 Transcription Factor, Histone, Oncology, 030220 oncology & carcinogenesis, MESH: Computational Biology, Chromatin Immunoprecipitation, Ribonucleoside Diphosphate Reductase, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Article, Adrenal tumours, MESH: Multivariate Analysis, 03 medical and health sciences, MESH: Cell Cycle Proteins, Cancer epigenetics, MESH: Cell Proliferation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Enhancer of Zeste Homolog 2 Protein, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Transcription factor, Cell Proliferation, Proportional Hazards Models, MESH: Humans, Cell growth, Computational Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Adenosine, Adrenal Cortex Neoplasms, MESH: Securin, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Multivariate Analysis, biology.protein, Cancer research, Chromatin immunoprecipitation, E2F1 Transcription Factor
Abstract: International audience; BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness. British Journal of Cancer https://doi.org/10.1038/s41416-019-0538-y BACKGROUND Adrenocortical carcinomas (ACC) are endocrine malignancies associated with dismal prognosis. At diagnosis, 80% of patients present metastases reducing the 5 years survival rate below 30% for most series.
Published: 2019
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9. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

Author: T. Dumontet, Antoine Martinez, Bruno Ragazzon, Anne-Marie Lefrançois-Martinez, Jean-Christophe Pointud, Nathanaëlle Montanier, Jérôme Bertherat, Igor Tauveron, Florence Roucher-Boulez, Isabelle Sahut-Barnola, Annabel Berthon, Damien Dufour, Pierre Val, Cyril Djari, M. Batisse-Lignier, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’endocrinologie diabétologie et maladies métaboliques, CHU Clermont-Ferrand, CHU Lyon, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d’Endocrinologie Diabète et Maladies Métaboliques [CHU Clermont-Ferrand], Pôle RHEUNNIRS [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Centre de référence des maladies rares de la surrénale ( CHU Cochin [AP-HP]), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), and Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, MESH: Neoplasm Proteins, MESH: Signal Transduction, MESH: beta Catenin, SUMO protein, MESH: Adrenal Cortex Neoplasms, Biochemistry, MESH: Mice, Knockout, Dexamethasone, MESH: Zona Fasciculata, Mice, 0302 clinical medicine, Cortex (anatomy), PKA, MESH: Animals, Cycloheximide, MESH: Cycloheximide, Wnt Signaling Pathway, beta Catenin, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Adrenal cortex, MESH: Sumoylation, MESH: Wnt Signaling Pathway, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, PIAS3.β-catenin, Cell biology, Neoplasm Proteins, medicine.anatomical_structure, MESH: Dexamethasone, Dactinomycin, Female, Zona Glomerulosa, Signal transduction, Biotechnology, Endocrine gland, Signal Transduction, MESH: Colforsin, MESH: Cell Line, Tumor, MESH: Mice, Transgenic, MESH: Zona Glomerulosa, MESH: Delayed-Action Preparations, Repressor, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Cyclic AMP-Dependent Protein Kinases, Biology, 03 medical and health sciences, MESH: Carney Complex, Adrenocorticotropic Hormone, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Animals, Humans, mouse models, Carney Complex, Molecular Biology, Psychological repression, MESH: Mice, MESH: Adrenocorticotropic Hormone, MESH: Humans, Colforsin, Sumoylation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, endocrine diseases, Cyclic AMP-Dependent Protein Kinases, Adrenal Cortex Neoplasms, MESH: Dactinomycin, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, SENP1/2, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Delayed-Action Preparations, MESH: Protein Processing, Post-Translational, Adrenal Cortex, MESH: Adrenal Cortex, Zona Fasciculata, Protein Processing, Post-Translational, MESH: Female, 030217 neurology & neurosurgery, Homeostasis
Abstract: SUMOylation is a highly conserved and dynamic post-translational mechanism primarily affecting nuclear programs for adapting organisms to stressful challenges. Alteration of SUMOylation cycles leads to severe developmental and homeostatic defects and malignancy, but signals coordinating SUMOylation are still unidentified. The adrenal cortex is a zonated endocrine gland that controls body homeostasis and stress response. Here, we show that in human and in mouse adrenals, SUMOylation follows a decreasing centripetal gradient that mirrors cortical differentiation flow and delimits highly and weakly SUMOylated steroidogenic compartments, overlapping glomerulosa, and fasciculata zones. Activation of PKA signaling by acute hormonal treatment, mouse genetic engineering, or in Carney complex results in repression of small ubiquitin-like modifier (SUMO) conjugation in the inner cortex by coordinating expression of SUMO pathway inducers and repressors. Conversely, genetic activation of canonical wingless-related integration site signaling maintains high SUMOylation potential in the outer neoplastic cortex. Thus, SUMOylation is tightly regulated by signaling pathways that orchestrate adrenal zonation and diseases.-Dumontet, T., Sahut-Barnola, I., Dufour, D., Lefrancois-Martinez, A.-M., Berthon, A., Montanier, N., Ragazzon, B., Djari, C., Pointud, J.-C., Roucher-Boulez, F., Batisse-Lignier, M., Tauveron, I., Bertherat, J., Val, P., Martinez, A. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.
Published: 2019
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10. Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

Author: T. Dumontet, Jean-Christophe Pointud, Anne-Marie Lefrançois-Martinez, Isabelle Sahut-Barnola, Cyril Djari, Igor Tauveron, Amandine Septier, Gwenneg Kerdivel, Christelle Damon-Soubeyrand, Coralie Drelon, Damien Richard, Annabel Berthon, Marie-Ange Calméjane, Pierre Val, Houda Tabbal, M. Batisse-Lignier, Antoine Martinez, Mickael Mathieu, Valentina Boeva, Stéphanie Rodriguez, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), CHU Gabriel Montpied (CHU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, endocrine system, Cellular differentiation, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, 03 medical and health sciences, 0302 clinical medicine, Zona fasciculata, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Adrenal insufficiency, Animals, Enhancer of Zeste Homolog 2 Protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Cyclic Nucleotide Phosphodiesterases, Type 7, Multidisciplinary, Adrenal cortex, Chemistry, EZH2, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cyclic Nucleotide Phosphodiesterases, Type 1, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 3, Cell biology, Mice, Inbred C57BL, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, medicine.anatomical_structure, PNAS Plus, Zona glomerulosa, 030220 oncology & carcinogenesis, Histone methyltransferase, Pka signaling, Adrenal Cortex, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, Female, Steroids, Zona Glomerulosa, Zona Fasciculata, Homeostasis, Signal Transduction
Abstract: International audience; Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endo-crine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phospho-diesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state. adrenal | differentiation | progenitors | PKA signaling | EZH2
Published: 2018
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11. P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model

Author: Antoine Martinez, Pierre Val, Igor Tauveron, J.-L. Kemeny, Coralie Drelon, T. Dumontet, Batisse-Lignier M, Mickael Mathieu, Jérôme Bertherat, Isabelle Sahut-Barnola, Christelle Damon-Soubeyrand, Anne-Marie Lefrançois-Martinez, Frédérique Tissier, G. Marceau, Jean-Christophe Pointud, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de physiologie digestive, urinaire, respiratoire et de l'exercice [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Hôpital Charles Nicolle [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Service de physiologie digestive, urinaire, respiratoire et de l'exercice [Rouen], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: 0301 basic medicine, Genetically modified mouse, Cancer Research, medicine.medical_specialty, Frizzled, Antigens, Polyomavirus Transforming, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, mTORC1, Biology, Mechanistic Target of Rapamycin Complex 1, Molecular oncology, Retinoblastoma Protein, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Corticosterone, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Adrenocortical Carcinoma, Adrenocortical carcinoma, Animals, Humans, Neoplasm Metastasis, Molecular Biology, Wnt Signaling Pathway, beta Catenin, ComputingMilieux_MISCELLANEOUS, Sirolimus, TOR Serine-Threonine Kinases, Wnt signaling pathway, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, Endocrinology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, 030220 oncology & carcinogenesis, Multiprotein Complexes, Signal transduction, Tumor Suppressor Protein p53
Abstract: Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Pan-genomic analyses identified p53/Rb and WNT/β-catenin signaling pathways as main contributors to the disease. However, isolated β-catenin constitutive activation failed to induce malignant progression in mouse adrenocortical tumors. Therefore, there still was a need for a relevant animal model to study ACC pathogenesis and to test new therapeutic approaches. Here, we have developed a transgenic mice model with adrenocortical specific expression of SV40 large T-antigen (AdTAg mice), to test the oncogenic potential of p53/Rb inhibition in the adrenal gland. All AdTAg mice develop large adrenal carcinomas that eventually metastasize to the liver and lungs, resulting in decreased overall survival. Consistent with ACC in patients, adrenal tumors in AdTAg mice autonomously produce large amounts of glucocorticoids and spontaneously activate WNT/β-catenin signaling pathway during malignant progression. We show that this activation is associated with downregulation of secreted frizzled related proteins (Sfrp) and Znrf3 that act as inhibitors of the WNT signaling. We also show that mTORC1 pathway activation is an early event during neoplasia expansion and further demonstrate that mTORC1 pathway is activated in ACC patients. Preclinical inhibition of mTORC1 activity induces a marked reduction in tumor size, associated with induction of apoptosis and inhibition of proliferation that results in normalization of corticosterone plasma levels in AdTAg mice. Altogether, these data establish AdTAg mice as the first preclinical model for metastatic ACC.
Published: 2017
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12. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD)

Author: T. Dumontet, Jean-Christophe Pointud, Pierre Val, Anne-Marie Lefrançois-Martinez, Constantine A. Stratakis, Jérôme Bertherat, Frédérique Tissier, Coralie Drelon, Isabelle Sahut-Barnola, Cyrille de Joussineau, M. Batisse-Lignier, Igor Tauveron, Antoine Martinez, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Pôle Endocrinologie-Diabétologie Adultes-Enfants, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), de Joussineau, Cyrille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Génétique, reproduction et développement (GReD), Université Blaise Pascal - Clermont-Ferrand 2 (UBP) - Université d'Auvergne - Clermont-Ferrand I (UdA) - IFR79 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP] - Hôpital Saint-Vincent de Paul, National Institutes of Health (NIH) - National Institute of Child Health and Human Development, Service d'Endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP] - Centre de Référence pour les Maladies Rares, Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Cochin [AP-HP]-Hôpital Saint-Vincent de Paul, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Cochin [AP-HP]-Centre de Référence pour les Maladies Rares, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôpital Saint-Vincent de Paul, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Centre de Référence pour les Maladies Rares
Subjects: Adrenal Cortex Diseases, Male, Tumor suppressor gene, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Hyperphosphorylation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, Gene Knockout Techniques, Mice, 03 medical and health sciences, 0302 clinical medicine, Adrenocorticotropic Hormone, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cell Line, Tumor, Genetics, Animals, Humans, Phosphorylation, Protein kinase A, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), PI3K/AKT/mTOR pathway, 030304 developmental biology, Sirolimus, 0303 health sciences, TOR Serine-Threonine Kinases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Articles, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell biology, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Disease Models, Animal, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Multiprotein Complexes, 030220 oncology & carcinogenesis, bcl-Associated Death Protein, Signal transduction, Signal Transduction, Primary pigmented nodular adrenocortical disease
Abstract: International audience; : Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which results in increased resistance to apoptosis that contributes to the tumorigenic process. We used in vitro and in vivo models to investigate the possibility of a crosstalk between PKA and mammalian target of rapamycin (mTOR) pathways in adrenocortical cells and its possible involvement in apoptosis resistance. Impact of PKA signaling on activation of the mTOR pathway and apoptosis was measured in a mouse model of PPNAD (AdKO mice), in human and mouse adrenocortical cell lines in response to pharmacological inhibitors and in PPNAD tissues by immunohistochemistry. AdKO mice showed increased mTOR complex 1 (mTORC1) pathway activity. Inhibition of mTORC1 by rapamycin restored sensitivity of adrenocortical cells to apoptosis in AdKO but not in wild-type mice. In both cell lines and mouse adrenals, rapid phosphorylation of mTORC1 targets including BAD proapoptotic protein was observed in response to PKA activation. Accordingly, BAD hyperphosphorylation, which inhibits its proapoptotic activity, was increased in both AdKO mouse adrenals and human PPNAD tissues. In conclusion, mTORC1 pathway is activated by PKA signaling in human and mouse adrenocortical cells, leading to increased cell survival, which is correlated with BAD hyperphosphorylation. These alterations could be causative of tumor formation.
Published: 2014
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13. EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression

Author: Pierre Val, T. Dumontet, Silvère Baron, Antoine Martinez, M. Batisse-Lignier, Jean Christophe Pointud, Mickael Mathieu, Anne Marie Lefrançois-Martinez, Bruno Ragazzon, Rork Kuick, Stéphanie Rodriguez, Annabel Berthon, Isabelle Sahut-Barnola, Houda Tabbal, Jérôme Bertherat, Coralie Drelon, Thomas J. Giordano, Amandine Septier, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche Universitaire Lorrain d'Histoire (CRULH), Université de Lorraine (UL), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: 0301 basic medicine, medicine.medical_treatment, MESH: beta Catenin, Gene Expression, MESH: Adrenal Cortex Neoplasms, MESH: Insulin-Like Growth Factor II, Mice, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Adrenocortical carcinoma, Mitotane, MESH: Animals, Wnt Signaling Pathway, beta Catenin, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, EZH2, Wnt signaling pathway, MESH: Genetic Predisposition to Disease, MESH: Wnt Signaling Pathway, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 030220 oncology & carcinogenesis, Histone methyltransferase, Disease Progression, RNA Interference, MESH: Disease Progression, Growth inhibition, Databases, Nucleic Acid, medicine.drug, MESH: Gene Expression, MESH: Cell Line, Tumor, MESH: Mice, Transgenic, MESH: RNA Interference, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Databases, Nucleic Acid, Article, 03 medical and health sciences, Insulin-Like Growth Factor II, Cell Line, Tumor, MESH: Cell Proliferation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Carcinoma, MESH: Enhancer of Zeste Homolog 2 Protein, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Genetic Predisposition to Disease, Molecular Biology, MESH: Mice, Cell Proliferation, MESH: Humans, Growth factor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Adrenal Cortex Neoplasms, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, Cancer research
Abstract: International audience; Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/β-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC.
Published: 2016
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14. Transcriptional Control of Adrenal Steroidogenesis

Author: Anne-Marie Lefrançois-Martinez, Nadine Binart, Antonine Blondet-Trichard, Jean-Christophe Pointud, Isabelle Sahut-Barnola, Céline Chambon, Antoine Martinez, Pierre Val, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Endocrinologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: endocrine system, medicine.medical_specialty, 030209 endocrinology & metabolism, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], CREB, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Corticosterone, Internal medicine, medicine, Cyclic AMP Response Element-Binding Protein, Protein kinase A, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Janus kinase 2, biology, Adrenal cortex, Tyrosine phosphorylation, Cell Biology, Endocrinology, medicine.anatomical_structure, chemistry, biology.protein, Janus kinase, hormones, hormone substitutes, and hormone antagonists
Abstract: In the adrenal gland, adrenocorticotropin (ACTH) acting through the cAMP protein kinase (PKA) transduction pathway is the main regulator of genes involved in glucocorticoid synthesis. The prolactin (PRL) receptor is expressed in the adrenal cortex of most mammals, but experimental proof that PRL ensures direct control on glucocorticoid synthesis in rodents remains elusive. To unravel the physiological importance of PRL in adrenocortical functions, we measured steroidogenic capacity of Prlr-deficient mice (Prlr−/−) and explored the influence of JAK/STAT signaling, the major PRL transduction pathway, on the steroidogenic activity of adrenocortical cell cultures. We demonstrate that lack of Prlr does not affect basal (nor stress-induced) corticosterone levels in mice. PRL triggers JAK2/STAT5-dependent transcription in adrenal cells, but this does not influence corticosterone release. In contrast, pharmacological or siRNA-mediated inhibition of JAK2 reveals its essential role in both basal and ACTH/cAMP-induced steroidogenesis. We demonstrate that nuclear JAK2 regulates the amount of active transcription factor CREB (cAMP response element-binding protein) through tyrosine phosphorylation and prevention of proteasomal degradation, which in turn leads to transcriptional activation of the rate-limiting steroidogenic Star gene. Hence, we describe a novel link between PKA and JAK2 by which nuclear JAK2 signaling controls adrenal steroidogenesis by increasing the stability of CREB.
Published: 2011
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15. Aldose Reductases Influence Prostaglandin F 2α Levels and Adipocyte Differentiation in Male Mouse and Human Species

Author: Isabelle Sahut-Barnola, Anne-Marie Lefrançois-Martinez, Karem Slim, Emilie Pastel, Jean-Christophe Pointud, Gwenaëlle Martin, Gaëlle Loubeau, Christian Dani, Antoine Martinez, Fanny Volat, Pierre Val, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Chirurgie digestive et hépatobiliaire, Centre Hospitalier Universitaire Estaing, CHU Estaing [Clermont-Ferrand], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CHU Clermont-Ferrand, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Adult, Male, Gene isoform, medicine.medical_specialty, Receptors, Prostaglandin, Adipose tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Dinoprost, Mice, chemistry.chemical_compound, Endocrinology, Aldehyde Reductase, 3T3-L1 Cells, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, Adipocyte, Gene expression, Adipocytes, medicine, Animals, Humans, Obesity, RNA, Messenger, Enzyme Inhibitors, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Aldose reductase, Adipogenesis, Gene Expression Profiling, Multipotent Stem Cells, Cell Differentiation, Cloprostenol, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Stromal vascular fraction, Subcutaneous Fat, Abdominal, Luteolytic Agents, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Adipose Tissue, Biochemistry, chemistry, Hydroxyprostaglandin Dehydrogenases, Phthalazines
Abstract: International audience; Aldose reductases (AKR1B) are widely expressed oxidoreductases whose physiological function remains elusive. Some isoforms are genuine prostaglandin F2α (PGF2α) synthases, suggesting they might influence adipose homeostasis because PGF2α inhibits adipogenesis. This was shown by Akr1b7 gene ablation in the mouse, which resulted in increased adiposity related to a lower PGF2α content in fat. Yet humans have no ortholog gene for Akr1b7, so the role of aldose reductases in human adipose homeostasis remains to be explored. We analyzed expression of genes encoding human and mouse aldose reductase isoforms in adipose tissues and differentiating adipocytes to assess conserved mechanisms regulating PGF2α synthesis and adipogenesis. The Akr1b3 gene encoded the most abundant isoform in mouse adipose tissue, whereas Akr1b7 encoded the only isoform enriched in the stromal vascular fraction. Most mouse aldose reductase gene expression peaked in early adipogenesis of 3T3-L1 cells and diminished with differentiation. In contrast with its mouse ortholog Akr1b3, AKR1B1 expression increased throughout differentiation of human multipotent adipose-derived stem cells, paralleling PGF2α release, whereas PGF2α receptor (FP) levels collapsed in early differentiation. Pharmacological inhibition of aldose reductase using Statil altered PGF2α production and enhanced human multipotent adipose-derived stem adipocyte differentiation. As expected, the adipogenic effects of Statil were counteracted by an FP agonist (cloprostenol). Thus, in both species aldose reductase-dependent PGF2α production could be important in early differentiation to restrict adipogenesis. PGF2α antiadipogenic signaling could then be toned down through the FP receptor or aldose reductases down-regulation in human and mouse cells, respectively. Our data suggest that aldose reductase inhibitors could have obesogenic potential.
Published: 2015
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16. Aldo-Keto Reductases 1B in Endocrinology and Metabolism

Author: Emilie Pastel, Jean-Christophe Pointud, Anne-Marie Lefrançois-Martinez, Fanny Volat, Antoine Martinez, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Gene isoform, medicine.medical_specialty, Adipose tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, Biology, prostaglandins, 03 medical and health sciences, 0302 clinical medicine, Polyol pathway, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Pharmacology (medical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, Regulation of gene expression, Pharmacology, 0303 health sciences, Aldose reductase, Aldo-keto reductase, aldose reductases, lcsh:RM1-950, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, adipose tissue, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Enzyme, Endocrinology, lcsh:Therapeutics. Pharmacology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, Biochemistry, Aldose, 030220 oncology & carcinogenesis, enterohepatic tissue, metabolism
Abstract: The aldose reductase (human AKR1B1/mouse Akr1b3) has been the focus of many research because of its role in diabetic complications. The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme. However, the issue of aldose reductase function in non-diabetic condition remains unresolved. Aldose reductase-like enzymes (AKR1B10, Akr1b7 and Akr1b8) are highly related isoforms often co-expressed with bona fide aldose reductase, making functional analysis of one or the other isoform a challenging task. AKR1B/Akr1b members share at least 65% protein identity and the general ability to reduce many redundant substrates such as aldehydes provided from lipid peroxidation, steroids and their by-products and xenobiotics in vitro. Based on these properties, AKR1B/Akr1b are generally considered as detoxifying enzymes. Considering that divergences should be more informative than similarities to help understanding their physiological functions, we chose to review specific hallmarks of each human/mouse isoforms by focusing on tissue distribution and specific mechanisms of gene regulation. Indeed, although the aldose reductase shows ubiquitous expression, aldose reductase-like proteins exhibit tissue-specific patterns of expression. We focused on 3 organs where certain isoforms are enriched, the adrenal gland, enterohepatic and adipose tissues and tried to connect recent enzymatic and regulation data with endocrine and metabolic functions of these organs. We presented recent mouse models showing unsuspected physiological functions in the regulation of glucido-lipidic metabolism and adipose tissue homeostasis. Beyond the widely accepted idea that AKR1B/Akr1b are detoxification enzymes, these recent reports provide growing evidences that they are able to modify or generate signal molecules. This conceptually shifts this class of enzymes from unenviable status of scavenger to upper class of messengers.
Published: 2012
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17. Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

Author: Jean-Christophe Pointud, Catherine Delarue, Hervé Lefebvre, François Coudoré, Antoine Martinez, Estelle Louiset, Sarah Lambert-Langlais, Isabelle Sahut-Barnola, Yoshihiro Urade, Fanny Volat, Bruno Ragazzon, M Manin, Pierre Val, Anne-Marie Lefrançois-Martinez, Unité de Nutrition Humaine (UNH), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), and Neuroendocrinologie cellulaire et moléculaire
Subjects: Male, Chromaffin Cells, Aldo-Keto Reductases, lcsh:Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Dinoprost, Diabetes and Endocrinology/Obesity, Mice, chemistry.chemical_compound, 0302 clinical medicine, Adrenal Glands, Diabetes and Endocrinology/Endocrinology, lcsh:Science, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Adrenal cortex, Adrenal gland, respiratory system, medicine.anatomical_structure, lipids (amino acids, peptides, and proteins), hormones, hormone substitutes, and hormone antagonists, Research Article, endocrine system, medicine.medical_specialty, Prostaglandin, Endocrine System, Adrenocorticotropic hormone, Biology, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Paracrine signalling, Diabetes and Endocrinology/Adrenal Cortex, Aldehyde Reductase, Internal medicine, medicine, Animals, Humans, Rats, Wistar, Autocrine signalling, Glucocorticoids, 030304 developmental biology, Aldo-keto reductase, Binding Sites, lcsh:R, Rats, Alcohol Oxidoreductases, Endocrinology, Glucocorticoid secretion, chemistry, Cyclooxygenase 2, lcsh:Q, 030217 neurology & neurosurgery
Abstract: Prostaglandin F(2alpha) (PGF(2alpha)), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF(2alpha) synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF(2alpha) biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF(2alpha) but expressed different biosynthetic isozymes. In chromaffin cells, PGF(2alpha) secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF(2alpha) secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF(2alpha) release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF(2alpha) receptor was only detected in chromaffin cells, making medulla the primary target of PGF(2alpha) action. By comparing PGF(2alpha)-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF(2alpha) repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF(2alpha) may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal.
Published: 2009
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18. Mouse model for bilateral adrenal hyperplasia

Author: G. Marceau, Bruno Ragazzon, Sarah Lambert-Langlais, Lawrence S. Kirschner, Anne-Marie Lefrançois-Martinez, Pierre Val, Jean-Christophe Pointud, Antoine Martinez, Jérôme Bertherat, C. A. Stratakis, Isabelle Sahut-Barnola, V. Sapin, C. De Joussineau, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Tumor suppressor gene, Endocrinology, Diabetes and Metabolism, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Biology, Article, Functional Laterality, Loss of heterozygosity, 03 medical and health sciences, Mice, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Endocrine system, Animals, PRKAR1A, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Adrenal Hyperplasia, Congenital, General Medicine, Hyperplasia, medicine.disease, Disease Models, Animal, 030220 oncology & carcinogenesis, Chromosomal region, Knockout mouse, Primary pigmented nodular adrenocortical disease
Abstract: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of bilateral hyperplasia leading to high morbidity due to pituitary-independent hypercortisolism and Cushing’s syndrome. PPNAD may be either sporadic or regarded as the most frequent endocrine manifestation of Carney’s complex (CNC), an autosomic dominant multiple neoplasia syndrome characterized by cardiac myxomas, spotty skin pigmentation and endocrine overactivity [1]. Both isolated PPNAD and CNC have been associated with null mutations in PRKAR1A, a gene encoding the type 1 αregulatory subunit (RIα) of the cAMP-dependent protein kinase (PKA) [2 and 3]. Tumor-specific loss of heterozygosity within the chromosomal region harboring PRKAR1A is observed in CNC patients and isolated PPNAD suggesting that PRKAR1A is a potential tumor suppressor gene [4]. Because general homozygous loss of Prkar1a is lethal in early mouse embryos [5], adrenal-specific knockout was required to demonstrate tumor suppressor activity. Therefore, we produced mice with Prkar1a gene inactivation in adrenocortical cells by mating Prkar1a floxed mice with the Akr1b7 -Cre mouse line, a novel Cre expressing line we developed to allow specific gene ablation in the steroidogenic lineage of the adrenals without affecting the gonads [6]. Adrenal cortex-specific Prkar1a knockout mice (AdKO) develop pituitary-independent Cushing’s syndrome and evident signs of deregulated adrenocortical cells differentiation and proliferation. These defects lead to improper maintenance and expansion of foetal adrenal cells in adult adrenals and establishment of pretumoral conditions. Our data provide the first in vivo evidence that the absence of RIα subunit of PKA is sufficient to explain autonomous adrenal hyperactivity and bilateral hyperplasia observed in PPNAD. They also strongly suggest that deregulated PKA activity positively affects the maintenance of foetal characters in adult glands.
Published: 2009
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19. The intracellular localisation of TAF7L, a paralogue of transcription factor TFIID subunit TAF7, is developmentally regulated during male germ-cell differentiation

Author: Lucia Monaco, Irwin Davidson, Stefano Brancorsini, Martti Parvinen, Gabrielle Mengus, Paolo Sassone-Corsi, and Jean-Christophe Pointud
Subjects: Intracellular Fluid, Male, Molecular Sequence Data, Gene Expression, macromolecular substances, Biology, Mice, medicine, Animals, Tissue Distribution, Amino Acid Sequence, Cloning, Molecular, Spermatogenesis, TATA-Binding Protein Associated Factors, General transcription factor, Sequence Homology, Amino Acid, fungi, Cell Biology, TAF7, TATA-Box Binding Protein, Molecular biology, Spermatozoa, TAF1, Protein Subunits, medicine.anatomical_structure, TAF4, Transcription Factor TFIID, TAF2, Female, Germ cell, Transcription factor II A
Abstract: Transcription regulation in male germ cells can involve specialised mechanisms and testis-specific paralogues of the general transcription machinery. Here we describe TAF7L, a germ-cell-specific paralogue of the TFIID subunit TAF7. TAF7L is expressed through most of the male germ-cell differentiation programme, but its intracellular localisation is dynamically regulated from cytoplasmic in spermatogonia and early spermatocytes to nuclear in late pachytene spermatocytes and haploid round spermatids. Import of TAF7L into the nucleus coincides with decreased TAF7 expression and a strong increase in nuclear TBP expression, which suggests that TAF7L replaces TAF7 as a TFIID subunit in late pachytene spermatocytes and in haploid cells. In agreement with this, biochemical experiments indicate that a subpopulation of TAF7L is tightly associated with TBP in both pachytene and haploid cells and TAF7L interacts with the TFIID subunit TAF1. We further show that TAF3, TAF4 and TAF10 are all strongly expressed in early spermatocytes, but that in contrast to TBP and TAF7L, they are downregulated in haploid cells. Hence,different subunits of the TFIID complex are regulated in distinct ways during male germ-cell differentiation. These results show for the first time how the composition of a general transcription factor such as TFIID and other TAF-containing complexes are modulated during a differentiation programme highlighting the unique nature of the transcription regulatory machinery in spermatogenesis.
Published: 2003

20. The BTB/POZ domain of the regulatory proteins Bric à brac 1 (BAB1) and Bric à brac 2 (BAB2) interacts with the novel Drosophila TAF(II) factor BIP2/dTAF(II)155

Author: Jan Larsson, Jean-Christophe Pointud, Bernard Dastugue, Jean-Louis Couderc, Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of microbiology, Umeå University, Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Couderc, Jean-Louis
Subjects: MESH : Molecular Sequence Data, Time Factors, MESH : Transcription Factors, Transcription, Genetic, MESH: Drosophila, MESH : Models, Genetic, Plasma protein binding, MESH : Blotting, Western, MESH: Protein Structure, Tertiary, Protein structure, Transcription (biology), Transcriptional regulation, Drosophila Proteins, MESH: Animals, transcriptional regulation, MESH: Models, Genetic, BTB/POZ domain, TAFII, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics, MESH : Blotting, Northern, MESH : Protein Binding, MESH: Transcription Factors, DNA-Binding Proteins, MESH: Repressor Proteins, Drosophila, MESH : DNA-Binding Proteins, MESH : Repressor Proteins, MESH : Protein Structure, Tertiary, Drosophila Protein, MESH : Time Factors, Plasmids, Protein Binding, MESH: Drosophila Proteins, Blotting, Western, Molecular Sequence Data, Biology, MESH: Two-Hybrid System Techniques, Chromatin remodeling, MESH: Plasmids, Two-Hybrid System Techniques, [SDV.BDD] Life Sciences [q-bio]/Development Biology, MESH: Blotting, Northern, MESH: Blotting, Western, MESH: Protein Binding, Animals, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, MESH : Drosophila, Transcription factor, Molecular Biology, MESH: Molecular Sequence Data, Models, Genetic, MESH: Transcription, Genetic, MESH: Time Factors, MESH : Transcription, Genetic, Cell Biology, MESH : Drosophila Proteins, Blotting, Northern, Protein Structure, Tertiary, Repressor Proteins, MESH : Two-Hybrid System Techniques, MESH : Plasmids, MESH : Animals, MESH: DNA-Binding Proteins, Developmental Biology, Transcription Factors
Abstract: International audience; The BTB/POZ domain is an evolutionarily conserved protein-protein interaction domain present in the N-terminal region of numerous transcription factors involved in development, chromatin remodeling, and human cancers. This domain is involved in homomeric and heteromeric associations with other BTB/POZ domains. The Drosophila BTB/POZ proteins Bric ?rac 1 (BAB1) and Bric ?rac 2 (BAB2) are developmentally regulated transcription factors which are involved in pattern formation along the proximo-distal axis of the leg and antenna, in the morphogenesis of the adult ovaries, and in the control of sexually dimorphic characters. We have identified partners of the BAB1 protein by using the two-hybrid system. The characterization of one of these proteins, called BIP2 for BAB Interacting Protein 2, is presented. BIP2 is a novel Drosophila TATA-box Protein Associated Factor (TAF(II)), also named dTAF(II)155. We show that the BTB/POZ domains of BAB1 and BAB2 are sufficient to mediate a direct interaction with BIP2/dTAF(II)155. This provides a direct link between these BTB/POZ transcription factors and the basal transcriptional machinery. We discuss the implications of the interaction between a BTB/POZ domain and a TAF(II) for the molecular mechanisms of transcriptional control mediated by BTB/POZ transcription factors.
Published: 2001
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21. The TFIID Components Human TAFII140 and Drosophila BIP2 (TAFII155) Are Novel Metazoan Homologues of Yeast TAFII47 Containing a Histone Fold and a PHD Finger

Author: Irwin Davidson, Jean-Christophe Pointud, Selen C. Muratoglu, Laszlo Tora, Christophe Romier, Jean-Louis Couderc, Yann-Gaël Gangloff, Lucie Carré, Marjorie Brand, Sylvie Thuault, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biosciences, and University of Exeter
Subjects: Time Factors, Xenopus, [SDV]Life Sciences [q-bio], Amino Acid Motifs, Salivary Glands, Histones, Mice, Transcription Factors, TFII, Candida albicans, Drosophila Proteins, Cloning, Molecular, Conserved Sequence, In Situ Hybridization, Zebrafish, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, biology, 030302 biochemistry & molecular biology, Temperature, Cell biology, TAF1, TAF4, Histone fold, COS Cells, Drosophila, Transcription factor II D, Dimerization, Drosophila Protein, Plasmids, animal structures, Saccharomyces cerevisiae Proteins, Molecular Sequence Data, Evolution, Molecular, 03 medical and health sciences, Two-Hybrid System Techniques, Animals, Humans, Amino Acid Sequence, Molecular Biology, 030304 developmental biology, TATA-Binding Protein Associated Factors, Transcriptional Regulation, Sequence Homology, Amino Acid, fungi, Genetic Complementation Test, Cell Biology, Precipitin Tests, Protein Structure, Tertiary, Microscopy, Fluorescence, Transcription Factor TFIID, biology.protein, Trans-Activators, TATA-binding protein, HeLa Cells, Transcription Factors
Abstract: The RNA polymerase II transcription factor TFIID comprises the TATA binding protein (TBP) and a set of TBP-associated factors (TAF(II)s). TFIID has been extensively characterized for yeast, Drosophila, and humans, demonstrating a high degree of conservation of both the amino acid sequences of the constituent TAF(II)s and overall molecular organization. In recent years, it has been assumed that all the metazoan TAF(II)s have been identified, yet no metazoan homologues of yeast TAF(II)47 (yTAF(II)47) and yTAF(II)65 are known. Both of these yTAF(II)s contain a histone fold domain (HFD) which selectively heterodimerizes with that of yTAF(II)25. We have cloned a novel mouse protein, TAF(II)140, containing an HFD and a plant homeodomain (PHD) finger, which we demonstrated by immunoprecipitation to be a mammalian TFIID component. TAF(II)140 shows extensive sequence similarity to Drosophila BIP2 (dBIP2) (dTAF(II)155), which we also show to be a component of Drosophila TFIID. These proteins are metazoan homologues of yTAF(II)47 as their HFDs selectively heterodimerize with dTAF(II)24 and human TAF(II)30, metazoan homologues of yTAF(II)25. We further show that yTAF(II)65 shares two domains with the Drosophila Prodos protein, a recently described potential dTAF(II). These conserved domains are critical for yTAF(II)65 function in vivo. Our results therefore identify metazoan homologues of yTAF(II)47 and yTAF(II)65.
Published: 2001
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21 results on '"Jean-Christophe Pointud"'

1. Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice

2. PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development

3. Aldo-keto reductases 1B in adrenal cortex physiology

4. Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice.

5. Aldo keto reductase 1B7 and prostaglandin F2alpha are regulators of adrenal endocrine functions.

6. Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

7. Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

8. EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness

9. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

10. Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

11. P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model

12. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD)

13. EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression

14. Transcriptional Control of Adrenal Steroidogenesis

15. Aldose Reductases Influence Prostaglandin F 2α Levels and Adipocyte Differentiation in Male Mouse and Human Species

16. Aldo-Keto Reductases 1B in Endocrinology and Metabolism

17. Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

18. Mouse model for bilateral adrenal hyperplasia

19. The intracellular localisation of TAF7L, a paralogue of transcription factor TFIID subunit TAF7, is developmentally regulated during male germ-cell differentiation

20. The BTB/POZ domain of the regulatory proteins Bric à brac 1 (BAB1) and Bric à brac 2 (BAB2) interacts with the novel Drosophila TAF(II) factor BIP2/dTAF(II)155

21. The TFIID Components Human TAFII140 and Drosophila BIP2 (TAFII155) Are Novel Metazoan Homologues of Yeast TAFII47 Containing a Histone Fold and a PHD Finger

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