The CDK4-pRB-E2F1 pathway controls insulin secretion

Autor:	Stéphane Dalle, Lluis Fajas, Safia Costes, Emilie Blanchet, Said Assou, Jean-Sébastien Annicotte, Irena Iankova, Claude Sardet, Carine Chavey, Jacques Teyssier
Přispěvatelé:	INSERM, U834, Montpellier, F-34298, France, Métabolisme et cancer, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Arnaud de Villeuneuve Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), INSERM-Association Française des Diabétiques (PNR-Diabète), Association pour la Recherche contre le Cancer, and Fondation pour la Recherche Médicale. E.B. is supported by a grant form the Ministère de l'Enseignement Supérieur et de la Recherche, C.C. is supported by a grant from the Agence Nationale pour la Recherche., Agence Nationale pour la Recherche (ANR physio2006),Agence Nationale pour la Recherche (ANR physio2006), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Agence Nationale pour la Recherche (ANR physio2006), Le Ster, Yves, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Rok vydání:	2008
Předmět:	[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] medicine.medical_treatment MESH : Blotting Western MESH : RNA Small Interfering MESH : E2F1 Transcription Factor MESH : Phosphorylation Mice 0302 clinical medicine Insulin Secretion Glucose homeostasis Insulin MESH: Animals ComputingMilieux_MISCELLANEOUS MESH: Chromatin Immunoprecipitation 0303 health sciences Retinoblastoma protein MESH : Reverse Transcriptase Polymerase Chain Reaction MESH : Protein Binding Transfection [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Immunohistochemistry Cell biology MESH: COS Cells [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] 030220 oncology & carcinogenesis COS Cells [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] endocrine system Blotting Western MESH: Insulin Article 03 medical and health sciences MESH: Gene Expression Profiling Islets of Langerhans [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] MESH: Blotting Western MESH: Protein Binding MESH : Islets of Langerhans Potassium Channels Inwardly Rectifying neoplasms MESH: Phosphorylation MESH : Glucose MESH: Islets of Langerhans MESH : Gene Expression Profiling MESH: Cercopithecus aethiops MESH: Cell Line Mice Inbred C57BL Insulin receptor Glucose MESH : Cercopithecus aethiops Chromatin immunoprecipitation MESH: Signal Transduction MESH : Cell Line MESH : Immunohistochemistry MESH : Insulin [SDV]Life Sciences [q-bio] MESH : Models Biological MESH: Mice Knockout Retinoblastoma Protein MESH: Reverse Transcriptase Polymerase Chain Reaction MESH: RNA Small Interfering Chlorocebus aethiops Phosphorylation RNA Small Interfering [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Mice Knockout biology [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Reverse Transcriptase Polymerase Chain Reaction MESH: Potassium Channels Inwardly Rectifying MESH: E2F1 Transcription Factor MESH: Glucose MESH : Cyclin-Dependent Kinase 4 Regulatory Pathway Signal transduction MESH : Transfection biological phenomena cell phenomena and immunity MESH : COS Cells Protein Binding Signal Transduction Chromatin Immunoprecipitation MESH: Cyclin-Dependent Kinase 4 MESH : Mice Inbred C57BL Models Biological Cell Line MESH : Chromatin Immunoprecipitation MESH: Mice Inbred C57BL MESH : Mice medicine [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Animals MESH: Mice 030304 developmental biology MESH : Signal Transduction MESH: Transfection Gene Expression Profiling MESH: Models Biological Cyclin-Dependent Kinase 4 MESH: Immunohistochemistry Cell Biology MESH: Retinoblastoma Protein MESH : Potassium Channels Inwardly Rectifying biology.protein MESH : Mice Knockout MESH : Animals MESH : Retinoblastoma Protein E2F1 Transcription Factor
Zdroj:	Nature Cell Biology Nature Cell Biology, Nature Publishing Group, 2009, 11 (8), pp.1017-1023. ⟨10.1038/ncb1915⟩ Nature Cell Biology, Nature Publishing Group, 2009, 11 (8), pp.1017-23. 〈10.1038/ncb1915〉 Nature Cell Biology, 2009, 11 (8), pp.1017-23. ⟨10.1038/ncb1915⟩ Nature Cell Biology, Nature Publishing Group, 2009, 11 (8), pp.1017-23. ⟨10.1038/ncb1915⟩
ISSN:	1476-4679 1465-7392
Popis:	International audience; CDK4-pRB-E2F1 cell-cycle regulators are robustly expressed in non-proliferating beta cells, suggesting that besides the control of beta-cell number the CDK4-pRB-E2F1 pathway has a role in beta-cell function. We show here that E2F1 directly regulates expression of Kir6.2, which is a key component of the K(ATP) channel involved in the regulation of glucose-induced insulin secretion. We demonstrate, through chromatin immunoprecipitation analysis from tissues, that Kir6.2 expression is regulated at the promoter level by the CDK4-pRB-E2F1 pathway. Consistently, inhibition of CDK4, or genetic inactivation of E2F1, results in decreased expression of Kir6.2, impaired insulin secretion and glucose intolerance in mice. Furthermore we show that rescue of Kir6.2 expression restores insulin secretion in E2f1(-/-) beta cells. Finally, we demonstrate that CDK4 is activated by glucose through the insulin pathway, ultimately resulting in E2F1 activation and, consequently, increased expression of Kir6.2. In summary we provide evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in glucose homeostasis, defining a new link between cell proliferation and metabolism.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8ff8a1404638ea3f738e39e2364f733d https://pubmed.ncbi.nlm.nih.gov/19597485 Zobrazit plný text záznamu