title: Downregulation of E2F1 during ER stress is required to induce apoptosis.
abstract: The endoplasmic reticulum (ER) has recently emerged as an alternative target to induce cell death in tumours, because prolonged ER stress results in the induction of apoptosis even in chemoresistant transformed cells. Here, we show that the DNA-damage-responsive pro-apoptotic factor E2F1 is unexpectedly downregulated during the ER stress-mediated apoptotic programme. E2F1 decline is a late event during the ER response and is mediated by the two unfolded protein response (UPR) sensors ATF6 and IRE1 (also known as ERN1). Whereas ATF6 directly interacts with the E2F1 promoter, IRE1 requires the involvement of the known E2F1 modulator E2F7, through the activation of its main target Xbp-1. Importantly, inhibition of the E2F1 decrease prevents ER-stress-induced apoptosis, whereas E2F1 knockdown efficiently sensitises cells to ER stress-dependent apoptosis, leading to the upregulation of two main factors in the UPR pro-apoptotic execution phase, Puma and Noxa (also known as BBC3 and PMAIP1, respectively). Our results point to a novel key role of E2F1 in the cell survival/death decision under ER stress, and unveil E2F1 inactivation as a valuable novel potential therapeutic strategy to increase the response of tumour cells to ER stress-based anticancer treatments.
authors.affiliation: National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Pagliarini
authors.affiliation: National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Giglio
authors.affiliation: National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardoni
authors.affiliation: Department of Biology, Unit of the Dulbecco Telethon Institute, University of Rome 'Tor Vergata', 00133 Rome, Italy Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Zio
authors.affiliation: National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy Department of Biological and Environmental Science and Technology (Di.S.Te.B.A.), University of Salento, 73100 Lecce, Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy Cellular and Developmental Lab, Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.affiliation: National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy Cellular and Developmental Lab, Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy marco.corazzari@uniroma2.it marco.corazzari@inmi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Corazzari
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: ATF6; Apoptosis; E2F; ER Stress; UPR