title: Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway.
abstract: Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanisms regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3) is regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β) pathway in a cell-autonomous and non-cell-autonomous manner. β3 levels are dynamically increased during oncogene-induced senescence (OIS) through CBX7 Polycomb regulation, and downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS), independently of its ligand-binding activity. Moreover, cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP) without affecting proliferation. Finally, we show an increase in β3 levels in a subset of tissues during aging. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.
authors.affiliation: Epigenetics & Cellular Senescence Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Rapisarda
authors.affiliation: Epigenetics & Cellular Senescence Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.
authors.forename: Michela
authors.initials: M
authors.lastname: Borghesan
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Miguela
authors.affiliation: Protein Analysis and Proteomics Group, The Francis Crick Institute, South Mimms EN6 3LD, UK.
authors.forename: Vesela
authors.initials: V
authors.lastname: Encheva
authors.affiliation: Protein Analysis and Proteomics Group, The Francis Crick Institute, South Mimms EN6 3LD, UK.
authors.forename: Ambrosius P
authors.initials: AP
authors.lastname: Snijders
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.
authors.forename: Amaia
authors.initials: A
authors.lastname: Lujambio
authors.affiliation: Epigenetics & Cellular Senescence Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK. Electronic address: a.ologhlen@qmul.ac.uk.
authors.forename: Ana
authors.initials: A
authors.lastname: O'Loghlen
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D002648:Child; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D007553:Isotope Labeling; D051379:Mice; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C503627:CBX7 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C061248:ITGB3 protein, human; D039661:Integrin beta3; D021122:Protein Subunits; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D063150:Polycomb Repressive Complex 1
keywords: CBX7; ITGB3; Palbociclib; SASP; TGFβ; aging; cilengitide; integrin; senescence; β3