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

Publication date: 7 March 2017
Source:Cell Reports, Volume 18, Issue 10
Author(s): Valentina Rapisarda, Michela Borghesan, Veronica Miguela, Vesela Encheva, Ambrosius P. Snijders, Amaia Lujambio, Ana O'Loghlen
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.

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Rapisarda et al. show that integrin β3 subunit expression induces senescence by activating TGF-β, while β3 knockdown overcomes senescence. β3 is dynamically upregulated in OIS and has ligand-independent activity. They also find a positive correlation between β3 levels and aging in a subset of tissues.


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