title: E2F transcription factor 1 regulates cellular and organismal senescence by inhibiting Forkhead box O transcription factors.
abstract: E2F1 and FOXO3 are two transcription factors that have been shown to participate in cellular senescence. Previous report reveals that E2F1 enhanced cellular senescence in human fibroblast cells, while FOXO transcription factors play against senescence by regulation reactive oxygen species scavenging proteins. However, their functional interplay has been unclear. Here we use E2F1 knock-out murine Embryonic fibroblasts (MEFs), knockdown RNAi constructs, and ectopic expression of E2F1 to show that it functions by negatively regulating FOXO3. E2F1 attenuates FOXO3-mediated expression of MnSOD and Catalase without affecting FOXO3 protein stability, subcellular localization, or phosphorylation by Akt. We mapped the interaction between E2F1 and FOXO3 to a region including the DNA binding domain of E2F1 and the C-terminal transcription-activation domain of FOXO3. We propose that E2F1 inhibits FOXO3-dependent transcription by directly binding FOXO3 in the nucleus and preventing activation of its target genes. Moreover, knockdown of the Caenorhabditis elegans E2F1 ortholog efl-1 significantly extends lifespan in a manner that requires the activity of the C. elegans FOXO gene daf-16. We conclude that there is an evolutionarily conserved signaling connection between E2F1 and FOXO3, which regulates cellular senescence and aging by regulating the activity of FOXO3. We speculate that drugs and/or therapies that inhibit this physical interaction might be good candidates for reducing cellular senescence and increasing longevity.
authors.affiliation: From the State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: From the State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Shengyi
authors.initials: S
authors.lastname: Peng
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: From the State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Haihe
authors.initials: H
authors.lastname: Ruan
authors.affiliation: From the State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Yanglu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Tie-Mei
authors.initials: TM
authors.lastname: Li
authors.affiliation: Biological Sciences, The University of Chicago, Chicago, Illinois 60637, and.
authors.forename: Ursula
authors.initials: U
authors.lastname: Adams
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian 116044, China.
authors.forename: Songshu
authors.initials: S
authors.lastname: Meng
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian 116044, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Bi
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Meng-Qiu
authors.initials: MQ
authors.lastname: Dong
authors.affiliation: From the State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, zqyuan@sun5.ibp.ac.cn.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D008136:Longevity / Q000235:genetics; D051379:Mice; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C493765:efl-1 protein, C elegans; D002374:Catalase; D013482:Superoxide Dismutase
keywords: E2F Transcription Factor; FOXO; Oxidative Stress; Senescence; Transcription Regulation