scholarly journals Prostaglandin F2α promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE

2008 ◽  
Vol 15 (10) ◽  
pp. 1619-1628 ◽  
Author(s):  
K M Jansen ◽  
G K Pavlath
Keyword(s):  
Cell Survival ◽  
Muscle Cell ◽  
Prostaglandin F2α ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Survival And Growth

Urokinase (uPA) Induces Endothelial Cell Survival Via the X-Linked Inhibitor of Apoptosis Protein (XIAP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3712-3712
Author(s):  
Gerald W. Prager ◽  
Patrick M. Brunner ◽  
Judit Mihaly ◽  
Yuri Koschelnick ◽  
Bernd R. Binder
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Cell Survival ◽  
Pi3 Kinase ◽  
Endothelial Cell Migration ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Xiap Expression ◽  
Apoptosis Protein

Abstract uPA plays an important role in angiogenesis: Originally, the urokinase system has been implicated to assist the angiogenic process by it’s proteolytic properties. It is now becoming increasingly evident that uPA additionally elicits many pro-angiogenic responses like differentiation, proliferation and cell migration in a non-proteolytic fashion via induction of intracellular signal transduction. In this study we demonstrate that in endothelial cells uPA protects against apoptosis by transcriptional upregulation of inhibitor of apoptosis proteins (IAPs), among them most prominently the X-linked inhibitor of apoptosis protein (XIAP). In contrast to canonical growth factors, like vascular endothelial growth factor (VEGF), uPA elicits anti-apoptosis independently of the PI3-kinase pathway. uPA-induced cell survival is dependent on the type of extracellular matrix used indicating the involvement of integrin adhesion receptors. Thereby, uPA induces phosphorylation of the CDC42 downstream effector p21-activated kinase 1 (PAK1), which leads to IkappaB kinase alpha (IKKa) phosphorylation, a prerequisite for NFkappaB activation. Blocking NFkappaB by using the specific NFkappaB inhibitor BAY 11–7082 or by adenoviral-mediated overexpression of its inhibitor, IkB, inhibits uPA-induced XIAP expression as well as uPA-induced cell survival. Downregulating XIAP expression by small interfering RNA techniques significantly reduces cell survival efficiencies of uPA in endothelial cells. From these data we conclude that uPA activation, which is a main player in endothelial cell migration and invasion, provides an additional, PI3-kinase independent cell survival mechanism.

X-Linked Inhibitor of Apoptosis Protein (XIAP) Supports Urokinase (uPA)-Induced Endothelial Cell Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5461-5461
Author(s):  
Gerald W Prager ◽  
Judit Mihaly ◽  
Patrick Brunner ◽  
Christoph Zielinski ◽  
Bernd Binder
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Cell Survival ◽  
Endothelial Cell Migration ◽  
Migration And Invasion ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Endothelial Cell Survival ◽  
Apoptosis Protein

Abstract High uPA expressing tumors are associated with poor prognosis. While a direct effect on tumor cell behavior is described, uPA has especially been shown to mediate (tumor-) angiogenesis. Originally, the urokinase system has been implicated to assist the angiogenic process by it’s proteolytic activities. It is now becoming increasingly evident that uPA additionally elicits a whole array pro-angiogenic responses like differentiation, proliferation and cell migration, independent of its proteolytic activity by inducing intracellular signal transduction. Here we show that uPA induces upregulation of inhibitor of apoptosis proteins (IAPs), which protects endothelial cells against apoptosis. Thereby, uPA-induced endothelial cell survival is mediated by transcriptional upregulation the X-linked inhibitor of apoptosis protein (XIAP), because downregulation of XIAP by small interfering RNA techniques significantly reduces uPA mediated cell survival efficiencies of uPA in endothelial cells. The antiapoptotic activity of uPA was dependent on the presence of uPAR and LRP, but independent of the PI3kinase pathway, while VEGF-dependent antiapoptosis is mainly PI3kinase dependent. uPA-induced cell survival is dependent on the type of extracellular matrix on which cells are attached used indicating the involvement of integrin adhesion receptors. TherebyConsistently, uPA induces phosphorylation of the CDC42 downstream effector p21-activated kinase 1 (PAK1), which leads to IkappaB kinase alpha (IKKa) phosphorylation, a prerequisite for NFkappaB activation. As a consequence, p52/p50 but not p65 is are translocated into the nucleus. Blocking NFkappaB by using the specific NFkappaB inhibitor BAY 11–7082 or by adenoviral-mediated overexpression of its inhibitor, IkB, inhibits uPA-induced XIAP expression as well as uPA-induced cell survival. From these data we conclude that uPA, which is a main player in endothelial cell migration and invasion, provides an additional, PI3-kinase independent but NFkappaB dependent cell survival mechanism.

Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 856-865 ◽  
Author(s):  
Emanuela Rosati ◽  
Rita Sabatini ◽  
Giuliana Rampino ◽  
Antonio Tabilio ◽  
Mauro Di Ianni ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Survival ◽  
Ex Vivo ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Inhibitor Of Apoptosis ◽  
Apoptosis Resistance ◽  
Inhibitor Of Apoptosis Protein ◽  
Xiap Expression ◽  
Apoptosis Protein

Abstract Notch signaling is involved in tumorigenesis, but its role in B–chronic lymphocytic leukemia (B-CLL) pathogenesis is not completely defined. This study examined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitutively activated in B-CLL cells, and its activation is further increased in B-CLL cells, which resist spontaneous apoptosis after 24-hour ex vivo culture. Notch stimulation by a soluble Jagged1 ligand increases B-CLL cell survival and is accompanied by increased nuclear factor–kappa B (NF-κB) activity and cellular inhibitor of apoptosis protein 2 (c-IAP2) and X-linked inhibitor of apoptosis protein (XIAP) expression. In contrast, Notch-signaling inhibition by the γ-secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering RNA accelerate spontaneous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduction of NF-κB activity and c-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target.

scholarly journals Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma

2002 ◽  
Vol 23 (6) ◽  
pp. 1017-1024 ◽  
Author(s):  
Gavin J. Gordon ◽  
Krishnarao Appasani ◽  
Jeremy P. Parcells ◽  
Nishit K. Mukhopadhyay ◽  
Michael T. Jaklitsch ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Survival ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Tumor Cell Survival

Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein

Blood ◽  
2009 ◽  
Vol 113 (6) ◽  
pp. 1383-1390 ◽  
Author(s):  
Gerald W. Prager ◽  
Judit Mihaly ◽  
Patrick M. Brunner ◽  
Yuri Koshelnick ◽  
Gunilla Hoyer-Hansen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Survival ◽  
Pi3 Kinase ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Mrna Stabilization ◽  
Endothelial Cell Survival ◽  
Iκb Kinase ◽  
Apoptosis Protein

AbstractUrokinase-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 IκB kinase α that leads to nuclear factor κB (NF-κB) p52 activation. Indeed, blocking NF-κB activation by using specific NF-κB 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-κB–dependent cell survival pathway.

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