Article: article from journal or magazin.
E2F transcription factor-1 regulates oxidative metabolism.
Nature Cell Biology
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.
Adipose Tissue, Brown/cytology, Adipose Tissue, Brown/metabolism, Animals, Cell Proliferation, Cells, Cultured, Cyclin-Dependent Kinase 4/genetics, Cyclin-Dependent Kinase 4/metabolism, DNA Methylation, E2F1 Transcription Factor/genetics, E2F1 Transcription Factor/metabolism, Embryo, Mammalian/cytology, Energy Metabolism, Fibroblasts/cytology, Fibroblasts/metabolism, Gene Expression Profiling, Immunoblotting, Mice, Mice, Knockout, Microscopy, Fluorescence, Mitochondria/metabolism, Muscle Fibers, Skeletal/cytology, Muscle Fibers, Skeletal/metabolism, Muscle, Skeletal/cytology, Muscle, Skeletal/metabolism, Myoblasts/cytology, Myoblasts/metabolism, Oxygen Consumption, RNA Interference, Retinoblastoma Protein/genetics, Retinoblastoma Protein/metabolism, Reverse Transcriptase Polymerase Chain Reaction
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