SerpinB2 is a serine protease inhibitor 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 levels are increased in senescent cells and serpinB2 is thus considered a senescence biomarker. In this study, by mimicking the elevated levels of serpinB2 in senescent cells, 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 affect senescence. We also showed that serpinB2 is a direct downstream target of p53 that is activated by the DNA damage response pathway. Significantly, serpinB2 bound to and stabilized p21 to mediate senescence in a proteasome-independent manner, indicating that serpinB2 has a direct role in senescence. Thus, this study reveals a unique mechanism by which serpinB2 maintains senescence through stabilization of p21 protein levels.
<p>Western blot analysis of ZEB1, E-cadherin and PKCalpha in ARHGAP18 knockout, ARHGAP18 re-expression, miR-200b stable expression and miR-200b-ARHGAP18 double stable expression cells and a schematic summary of the mechanism of miR-200b inhibition of TNBC cell migration and tumor metastasis</p>
<p>ARHGAP18 re-expression in miR-200b stably expressing cells reverses the effect of miR-200b on actin cytoskeleton reorganization and RhoA activation</p>
<p>ARHGAP18 expression levels are significantly higher in TNBC tumors than other subtypes of breast cancer and higher ARHGAP18 levels in breast tumors are associated with poorer metastasis free survival.</p>
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