title: E2F transcription factor-1 regulates oxidative metabolism.
abstract: Cells respond to stress by coordinating proliferative and metabolic pathways. Starvation restricts cell proliferative (glycolytic) and activates energy productive (oxidative) pathways. Conversely, cell growth and proliferation require increased glycolytic and decreased oxidative metabolism levels. E2F transcription factors regulate both proliferative and metabolic genes. E2Fs have been implicated in the G1/S cell-cycle transition, DNA repair, apoptosis, development and differentiation. In pancreatic β-cells, E2F1 gene regulation facilitated glucose-stimulated insulin secretion. Moreover, mice lacking E2F1 (E2f1(-/-)) were resistant to diet-induced obesity. Here, we show that E2F1 coordinates cellular responses by acting as a regulatory switch between cell proliferation and metabolism. In basal conditions, E2F1 repressed key genes that regulate energy homeostasis and mitochondrial functions in muscle and brown adipose tissue. Consequently, E2f1(-/-) mice had a marked oxidative phenotype. An association between E2F1 and pRB was required for repression of genes implicated in oxidative metabolism. This repression was alleviated in a constitutively active CDK4 (CDK4(R24C)) mouse model or when adaptation to energy demand was required. Thus, E2F1 represents a metabolic switch from oxidative to glycolytic metabolism that responds to stressful conditions.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.|IGMM, Institut de Génétique Moléculaire de Montpellier, Montpellier, F-34293, France; CNRS, UMR5535, Montpellier, F-34293, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Blanchet
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.|IGMM, Institut de Génétique Moléculaire de Montpellier, Montpellier, F-34293, France; CNRS, UMR5535, Montpellier, F-34293, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Annicotte
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.|IGMM, Institut de Génétique Moléculaire de Montpellier, Montpellier, F-34293, France; CNRS, UMR5535, Montpellier, F-34293, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Lagarrigue
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Aguilar
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.
authors.forename: Cyrielle
authors.initials: C
authors.lastname: Clapé
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.|IGMM, Institut de Génétique Moléculaire de Montpellier, Montpellier, F-34293, France; CNRS, UMR5535, Montpellier, F-34293, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Chavey
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.|IGMM, Institut de Génétique Moléculaire de Montpellier, Montpellier, F-34293, France; CNRS, UMR5535, Montpellier, F-34293, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fritz
authors.affiliation: INRA, UMR0866, Montpellier, F-34060, France.
authors.forename: François
authors.initials: F
authors.lastname: Casas
authors.affiliation: INSERM U844, Montpellier, F-34295, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Apparailly
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, 1115 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France; Université de Montpellier1, Montpellier, F-34298, France; CRLC Val d'Aurelle Paul Lamarque, Montpellier, F-34298, France.|IGMM, Institut de Génétique Moléculaire de Montpellier, Montpellier, F-34293, France; CNRS, UMR5535, Montpellier, F-34293, France.
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
mesh_terms: D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D004734:Energy Metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010101:Oxygen Consumption; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016160:Retinoblastoma Protein; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4