Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway

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 beta 3) is regulated by the Polycomb protein CBX7. beta 3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor beta (TGF-beta) pathway in a cell-autonomous and non-cell-autonomous manner. beta 3 levels are dynamically increased during oncogene-induced senescence (OIS) through CBX7 Polycomb regulation, and downregulation of beta 3 levels overrides OIS and therapy-induced senescence (TIS), independently of its ligand-binding activity. Moreover, cilengitide, an alpha v beta 3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP) without affecting proliferation. Finally, we showan increase in beta 3 levels in a subset of tissues during aging. Altogether, our data show that integrin beta 3 subunit is a marker and regulator of senescence.