title: Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells.
abstract: Metabolism is closely linked with cellular state and biological processes, but the mechanisms controlling metabolic properties in different contexts remain unclear. Cellular senescence is an irreversible growth arrest induced by various stresses, which exhibits active secretory and metabolic phenotypes. Here, we show that retinoblastoma protein (RB) plays a critical role in promoting the metabolic flow by activating both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) in cells that have undergone oncogene-induced senescence (OIS). A combination of real-time metabolic monitoring, and metabolome and gene expression analyses showed that OIS-induced fibroblasts developed an accelerated metabolic flow. The loss of RB downregulated a series of glycolytic genes and simultaneously reduced metabolites produced from the glycolytic pathway, indicating that RB upregulates glycolytic genes in OIS cells. Importantly, both mitochondrial OXPHOS and glycolytic activities were abolished in RB-depleted or downstream glycolytic enzyme-depleted OIS cells, suggesting that RB-mediated glycolytic activation induces a metabolic flux into the OXPHOS pathway. Collectively, our findings reveal that RB essentially functions in metabolic remodeling and the maintenance of the active energy production in OIS cells.
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.|Program for Leading Graduate Schools 'HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program', Kumamoto University, Kumamoto, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takebayashi
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Hino
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Igata
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Masashi
authors.initials: M
authors.lastname: Narita
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.|Program for Leading Graduate Schools 'HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program', Kumamoto University, Kumamoto, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D016160:Retinoblastoma Protein
keywords: gene regulation; glycolysis; metabolic remodeling; oncogene-induced senescence; oxidative phosphorylation; retinoblastoma protein