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Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells

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 phenoty...

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Autores principales: Takebayashi, Shin-ichiro, Tanaka, Hiroshi, Hino, Shinjiro, Nakatsu, Yuko, Igata, Tomoka, Sakamoto, Akihisa, Narita, Masashi, Nakao, Mitsuyoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531082/
https://www.ncbi.nlm.nih.gov/pubmed/26009982
http://dx.doi.org/10.1111/acel.12351
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author Takebayashi, Shin-ichiro
Tanaka, Hiroshi
Hino, Shinjiro
Nakatsu, Yuko
Igata, Tomoka
Sakamoto, Akihisa
Narita, Masashi
Nakao, Mitsuyoshi
author_facet Takebayashi, Shin-ichiro
Tanaka, Hiroshi
Hino, Shinjiro
Nakatsu, Yuko
Igata, Tomoka
Sakamoto, Akihisa
Narita, Masashi
Nakao, Mitsuyoshi
author_sort Takebayashi, Shin-ichiro
collection PubMed
description 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.
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spelling pubmed-45310822015-08-13 Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells Takebayashi, Shin-ichiro Tanaka, Hiroshi Hino, Shinjiro Nakatsu, Yuko Igata, Tomoka Sakamoto, Akihisa Narita, Masashi Nakao, Mitsuyoshi Aging Cell Original Articles 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. John Wiley & Sons, Ltd 2015-08 2015-05-25 /pmc/articles/PMC4531082/ /pubmed/26009982 http://dx.doi.org/10.1111/acel.12351 Text en © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Takebayashi, Shin-ichiro
Tanaka, Hiroshi
Hino, Shinjiro
Nakatsu, Yuko
Igata, Tomoka
Sakamoto, Akihisa
Narita, Masashi
Nakao, Mitsuyoshi
Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells
title Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells
title_full Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells
title_fullStr Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells
title_full_unstemmed Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells
title_short Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells
title_sort retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531082/
https://www.ncbi.nlm.nih.gov/pubmed/26009982
http://dx.doi.org/10.1111/acel.12351
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