Deregulation of anti-Mullerian hormone/BMP and transforming growth factor- pathways in Leydig cell lesions developed in male heterozygous multiple endocrine neoplasia type 1 mutant mice
| Autor: | Séverine Mazaud Guittot, Sandra Fontanière, Alain Calender, Nader Hussein, Anne-Marie Morera, Nathalie di Clemente, Huguette Casse, Jieli Lu, Chang X. Zhang |
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| Přispěvatelé: | Génétique moléculaire, signalisation et cancer (GMSC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, CNRS UMR5201, Laboratoire de Génétique Moléculaire, International Agency for Cancer Research (IACR), Communications Cellulaires et Différenciation (CCD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de Génétique Moléculaire et Clinique, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Endocrinologie et Génétique de la Reproduction et du Développement, Université Paris-Sud - Paris 11 (UP11)-IFR13-Institut National de la Santé et de la Recherche Médicale (INSERM), The E-Institute of Shanghai, Xi'an Jiaotong University (Xjtu)-Sino-French Life Science and Genomic Research Center, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA) |
| Rok vydání: | 2008 |
| Předmět: |
Anti-Mullerian Hormone
Male endocrine system diseases Endocrinology Diabetes and Metabolism Messenger/metabolism Immunoenzyme Techniques Mice 0302 clinical medicine Endocrinology Transforming Growth Factor beta MESH: Animals Smad Proteins/metabolism 0303 health sciences Cyclin-Dependent Kinase Inhibitor p27/metabolism MESH: Multiple Endocrine Neoplasia Type 1/metabolism MESH: RNA Messenger/metabolism [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Multiple Endocrine Neoplasia Type 1/metabolism Oncology 030220 oncology & carcinogenesis Western Cyclin-Dependent Kinase Inhibitor p27 Leydig Cell Tumor endocrine system Knockout Blotting Western Luciferases/metabolism Bone morphogenetic protein 03 medical and health sciences MESH: Plasmids Cyclin-Dependent Kinase Inhibitor p18 MESH: Blotting Northern MESH: Blotting Western RNA Messenger MESH: Immunoenzyme Techniques MESH: Anti-Mullerian Hormone/metabolism medicine.disease Peptide/metabolism Messenger/genetics Carcinogenesis Receptors Transforming Growth Factor beta Cancer Research MESH: Bone Morphogenetic Proteins/metabolism Leydig Cell Tumor/metabolism Smad Proteins MESH: Leydig Cell Tumor/metabolism medicine.disease_cause MESH: Mice Knockout MESH: Reverse Transcriptase Polymerase Chain Reaction Receptors Northern Luciferases Multiple endocrine neoplasia Receptor MESH: Heterozygote Mice Knockout MESH: Smad Proteins/metabolism MESH: Receptors Peptide/metabolism Leydig cell biology Blotting Reverse Transcriptase Polymerase Chain Reaction Anti-Müllerian hormone MESH: Luciferases/metabolism medicine.anatomical_structure Bone Morphogenetic Proteins MESH: RNA Messenger/genetics Transforming Growth Factor beta/metabolism Plasmids Heterozygote congenital hereditary and neonatal diseases and abnormalities Receptors Peptide Multiple Endocrine Neoplasia Type 1/pathology Proto-Oncogene Proteins Multiple Endocrine Neoplasia Type 1 medicine Animals Cyclin-Dependent Kinase Inhibitor p18/metabolism Immunoprecipitation MEN1 MESH: Receptors Transforming Growth Factor beta/metabolism Anti-Mullerian Hormone/metabolism MESH: Mice 030304 developmental biology MESH: Cyclin-Dependent Kinase Inhibitor p27/metabolism MESH: Immunoprecipitation MESH: Proto-Oncogene Proteins/metabolism Bone Morphogenetic Proteins/metabolism Transforming growth factor beta Blotting Northern Proto-Oncogene Proteins/metabolism MESH: Male Leydig Cell Tumor/pathology Cancer research biology.protein RNA MESH: Leydig Cell Tumor/pathology MESH: Multiple Endocrine Neoplasia Type 1/pathology MESH: Cyclin-Dependent Kinase Inhibitor p18/metabolism MESH: Transforming Growth Factor beta/metabolism |
| Zdroj: | Endocrine-Related Cancer Endocrine-Related Cancer, BioScientifica, 2008, 15 (1), pp. 217-27. ⟨10.1677/ERC-06-0046⟩ |
| ISSN: | 1479-6821 1351-0088 |
| DOI: | 10.1677/erc-06-0046 |
| Popis: | International audience; Multiple endocrine neoplasia type 1 (MEN1) results from the mutation of the predisposing gene, MEN1. Heterozygous Men1 mutant mice previously generated by several laboratories, including ours, mimic largely MEN1 pathology. Interestingly, our heterozygous Men1 mutant mice exhibit not only the endocrine tumours commonly seen in MEN1 patients, but also Leydig cell tumours (LCT) with high frequency, accompanied systematically by loss of the wild-type Men1 allele. As there exists a similarity of tumour phenotype between these mice and those mutated for the components of anti-Mullerian hormone (AMH)/bone morphogenic protein (BMP) pathway belonging to transforming growth factor-beta (TGF-beta) family, we investigated the expression and the activity of this pathway, known to have an important biological role in Leydig cells. Here, we report that the expression of AMH receptor type 2 is reduced in Men1 LCTs. Both immunostaining and western blot analyses also demonstrate a markedly decreased nuclear expression of Smad1, 3, 4 and 5 in the tumours. More interestingly, we show that the reconstituted menin expression in Men1-deficient Leydig cells derived from LCTs can significantly increase the transcriptional activity of a BMP pathway target promoter, XVent2. Furthermore, we found that the expression of p18, p27 and cyclin dependant kinase 4 (Cdk4), targets of TGF-beta pathways, is altered in the Leydig cell lesions. Our data provide the evidence of the deregulation of AMH/BMP and TGF-beta pathways in mouse Men1 LCTs, highlighting their involvement in tumorigenesis of Leydig cells due to Men1 inactivation. |
| Databáze: | OpenAIRE |
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