Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway
Valentina Rapisarda,
Michela Borghesan,
Veronica Miguela,
Vesela Encheva,
Ambrosius P. Snijders,
Amaia Lujambio,
Ana O’Loghlen
Affiliations
Valentina Rapisarda
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
Michela Borghesan
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
Veronica Miguela
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA
Vesela Encheva
Protein Analysis and Proteomics Group, The Francis Crick Institute, South Mimms EN6 3LD, UK
Ambrosius P. Snijders
Protein Analysis and Proteomics Group, The Francis Crick Institute, South Mimms EN6 3LD, UK
Amaia Lujambio
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA
Ana O’Loghlen
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
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.
