E2F transcription factor-1 regulates oxidative metabolism

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 (CDK4R24C) 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.

[1]  J. Auwerx,et al.  Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure , 2007, Proceedings of the National Academy of Sciences.

[2]  J. Auwerx,et al.  Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (-/- )mice. , 2004, The Journal of clinical investigation.

[3]  Jeffrey T. Chang,et al.  A Combinatorial Mechanism for Determining the Specificity of E2F Activation and Repression , 2009, Oncogene.

[4]  J. Auwerx,et al.  E2Fs regulate adipocyte differentiation. , 2002, Developmental cell.

[5]  A. Russell,et al.  Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1α and PPARβ/δ gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus , 2007, International Journal of Obesity.

[6]  S. Culine,et al.  Peroxisome Proliferator-Activated Receptor γ Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer , 2006, Molecular and Cellular Biology.

[7]  M. Poutanen,et al.  The Transcriptional Corepressor RIP140 Regulates Oxidative Metabolism in Skeletal Muscle , 2007, Cell metabolism.

[8]  J. Auwerx,et al.  Impaired pancreatic growth, β cell mass, and β cell function in E2F1 –/– mice , 2004 .

[9]  B. Spiegelman,et al.  PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. , 2007, Genes & development.

[10]  R. Evans,et al.  Regulation of Muscle Fiber Type and Running Endurance by PPARδ , 2004, PLoS biology.

[11]  P D Gollnick,et al.  Enzyme activity and fiber composition in skeletal muscle of untrained and trained men. , 1972, Journal of applied physiology.

[12]  M. Bureau,et al.  High-efficiency gene transfer into skeletal muscle mediated by electric pulses. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Wallace.  A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine , 2005, Annual review of genetics.

[14]  P. Puigserver,et al.  Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α , 2006, Cell.

[15]  A. Russell,et al.  Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1 alpha and PPAR beta/delta gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus. , 2007, International journal of obesity.

[16]  C. Sardet,et al.  The CDK4–pRB–E2F1 pathway controls insulin secretion , 2009, Nature Cell Biology.

[17]  B. Spiegelman,et al.  PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy , 2007 .

[18]  C. Reggiani,et al.  Molecular diversity of myofibrillar proteins: gene regulation and functional significance. , 1996, Physiological reviews.

[19]  N. Dyson,et al.  Molecular mechanisms of E2F-dependent activation and pRB-mediated repression , 2004, Journal of Cell Science.

[20]  P. Bénit,et al.  S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. , 2007, Cell metabolism.

[21]  J. Auwerx,et al.  Pancreatic-Duodenal Homeobox 1 Regulates Expression of Liver Receptor Homolog 1 during Pancreas Development , 2003, Molecular and Cellular Biology.

[22]  L. Fajas,et al.  Cyclin D3 Promotes Adipogenesis through Activation of Peroxisome Proliferator-Activated Receptor γ , 2005, Molecular and Cellular Biology.

[23]  J. Pipas,et al.  E2F1-3 Switch from Activators in Progenitor Cells to Repressors in Differentiating Cells , 2009, Nature.

[24]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[25]  F. Casas,et al.  Overexpression of the Mitochondrial T3 Receptor p43 Induces a Shift in Skeletal Muscle Fiber Types , 2008, PloS one.

[26]  N. Dyson,et al.  The E2F transcriptional network: old acquaintances with new faces , 2005, Oncogene.

[27]  Jiandie D. Lin,et al.  Peroxisome Proliferator-activated Receptor γ Coactivator 1β (PGC-1β), A Novel PGC-1-related Transcription Coactivator Associated with Host Cell Factor* , 2002, The Journal of Biological Chemistry.

[28]  Marta García,et al.  NFAT isoforms control activity-dependent muscle fiber type specification , 2009, Proceedings of the National Academy of Sciences.

[29]  M. Vidal,et al.  E2Fs and the Retinoblastoma Protein Family , 1997 .

[30]  Seiichi Mori,et al.  An E2F1-dependent gene expression program that determines the balance between proliferation and cell death. , 2008, Cancer cell.

[31]  Jiandie D. Lin,et al.  Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. , 2002, The Journal of biological chemistry.

[32]  K. Kristiansen,et al.  The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation. , 2002, Developmental cell.