| First Author | Prager GW | Year | 2009 |
| Journal | Blood | Volume | 113 |
| Issue | 6 | Pages | 1383-90 |
| PubMed ID | 18948573 | Mgi Jnum | J:145580 |
| Mgi Id | MGI:3835252 | Doi | 10.1182/blood-2008-06-164210 |
| Citation | Prager GW, et al. (2009) Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein. Blood 113(6):1383-90 |
| abstractText | Urokinase-type plasminogen activator (uPA) additionally elicits a whole array of pro-angiogenic responses, such as differentiation, proliferation, and migration. In this study, we demonstrate that in endothelial cells uPA also protects against apoptosis by transcriptional up-regulation and partially by mRNA stabilization of inhibitor of apoptosis proteins, most prominently the X-linked inhibitor of apoptosis protein (XIAP). The antiapoptotic activity of uPA was dependent on its protease activity, the presence of uPA receptor (uPAR) and low-density lipoprotein receptor-related protein (LRP), but independent of the phosphatidylinositol 3 (PI3) kinase pathway, whereas vascular endothelial growth factor (VEGF)-induced antiapoptosis was PI3 kinase dependent. uPA-induced cell survival involved phosphorylation of p21-activated kinase 1 (Pak1) and the IkappaB kinase alpha that leads to nuclear factor kappaB (NF-kappaB) p52 activation. Indeed, blocking NF-kappaB activation by using specific NF-kappaB inhibitors abolished uPA-induced cell survival as it blocked uPA-induced XIAP up-regulation. Furthermore, down-regulating XIAP expression by small interfering RNA (siRNA) significantly reduced uPA-dependent endothelial cell survival. This mechanism is also important for VEGF-induced antiapoptosis because VEGF-dependent up-regulation of XIAP was found defective in uPA(-/-) endothelial cells. This led us to conclude that uPA is part of a novel NF-kappaB-dependent cell survival pathway. |
