Serine protease inhibitor SerpinB2 binds and stabilizes p21 in senescent cells

SerpinB2 is a serine protease inhibitor that is also known as plasminogen activator inhibitor type 2 (PAI-2). It has been well documented that SerpinB2 is an inhibitor of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA). Interestingly, SerpinB2 level is increased in senescent cells and is considered a senescence biomarker. Through mimicking the elevated level of SerpinB2 in senescent cells, this study showed the proliferating human fibroblasts were induced into senescence. Senescence induced by SerpinB2 did not relate to its extracellular function as inhibition of SerpinB2 secretion, exogenous introduced SerpinB2, or a SerpinB2 mutant that failed to bind to its extracellular target uPA, did not have an effect on senescence. This study also showed SerpinB2 is a direct downstream target of p53 that is activated through the DNA damage response pathway. Significantly, SerpinB2 bound to and stabilized p21 to mediate senescence in a proteasome-independent manner, indicating SerpinB2 has a direct role in senescence. Thus, this study reveals a unique mechanism that SerpinB2 maintains senescence through stabilization of the p21 protein level.