When cells have reached their proliferative capacity, they enter the terminal, non-dividing state of cellular senescence. In human fibroblasts, senescence is promoted by the tumour suppressor p53 and mediated by cell cycle inhibitors of the DNA damage response pathway, either p16 or p21. SerpinB2 is an inhibitor of urokinase plasminogen activator (uPA) and it had been reported that serpinB2 levels were elevated in senescent human skin fibroblasts. On page 3272, Jing-Jer Lin and co-workers identify a role for serpinB2 in senescence. They ectopically expressed serpinB2 in young fibroblasts, which induced senescence. This phenotype is not due to the extracellular function of serpinB2, as shown by the inhibition of serpinB2 secretion or both the introduction of exogenous serpinB2 and use of a mutant that does not bind extracellular uPA. Importantly, serpinB2 is a direct downstream target of p53 and can be induced by the DNA damage response pathway. The authors show that p21 is a direct binding partner and stabiliser of serpinB2 to promote senescence. This study provides new insights into the mechanism of senescence by demonstrating the capacity of the serine protease inhibitor serpinB2 to induce senescence and its role in senescence maintenance through the stabilization of p21 in fibroblasts.
