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      Molecular Mediators of α vβ 3-Induced Endothelial Cell Survival

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          The α<sub>v</sub>β<sub>3</sub> integrin interaction with the extracellular matrix (ECM) plays an essential role in inhibiting apoptosis in endothelial cells. We have recently shown that α<sub>v</sub>β<sub>3</sub> ligation on rat aortic endothelial cells (RAECs) specifically activates the transcription factor nuclear factor ĸB (NF-ĸB) and promotes cell survival. Inhibiting NF-ĸB nuclear translocation abolished the protective effect of α<sub>v</sub>β<sub>3</sub> ligands. Here, we report that ligation of α<sub>v</sub>β<sub>3 </sub>by its ligand, osteopontin (OPN), induces the phosphorylation and activation of inhibitory kappa B kinase beta (IKKβ) and promotes the specific degradation of inhibitory kappa Bα (IĸBα) in RAECs. Overexpression of a dominant negative (DN) IKKβ protein prevents IĸBα phosphorylation, NF-ĸB activation, and inhibits the protective effects of OPN. The NF-ĸB-inducing kinase (NIK) has been shown to be one of the upstream kinases involved in IKK activation. OPN-mediated NF-ĸB activity is increased upon NIK wild-type (WT) overexpression and blocked following NIK DN overexpression. In addition, NIK –/– mouse embryonic fibroblasts (MEFs) plated on OPN display reduced NF-ĸB activity and decreased IĸBα phosphorylation compared to NIK +/+ MEFs. Finally, functional inhibition of integrin β<sub>3</sub>-dependent NF-ĸB signaling decreases OPN-induced IĸBα, IKKβ and NIK phosphorylation. These studies for the first time show that the α<sub>v</sub>β<sub>3</sub>-NF-ĸB-dependent endothelial survival pathway is dependent on IĸBα, IKKβ, and NIK.

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          Most cited references 60

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          Disruption of epithelial cell-matrix interactions induces apoptosis

           S. Francis,  SM Frisch (1994)
          Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate cell number and tissue organization. It was therefore of interest to determine whether cell- matrix interactions affect apoptosis. The present report demonstrates that apoptosis was induced by disruption of the interactions between normal epithelial cells and extracellular matrix. We have termed this phenomenon "anoikis." Overexpression of bcl-2 protected cells against anoikis. Cellular sensitivity to anoikis was apparently regulated: (a) anoikis did not occur in normal fibroblasts; (b) it was abrogated in epithelial cells by transformation with v-Ha-ras, v-src, or treatment with phorbol ester; (c) sensitivity to anoikis was conferred upon HT1080 cells or v-Ha-ras-transformed MDCK cells by reverse- transformation with adenovirus E1a; (d) anoikis in MDCK cells was alleviated by the motility factor, scatter factor. The results suggest that the circumvention of anoikis accompanies the acquisition of anchorage independence or cell motility.
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            NF-κB: Ten Years After

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              MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1.

              Several members of the tumour-necrosis/nerve-growth factor (TNF/NGF) receptor family activate the transcription factor NF-kappaB through a common adaptor protein, Traf2 (refs 1-5), whereas the interleukin 1 type-I receptor activates NF-kappaB independently of Traf2 (ref. 4). We have now cloned a new protein kinase, NIK, which binds to Traf2 and stimulates NF-kappaB activity. This kinase shares sequence similarity with several MAPKK kinases. Expression in cells of kinase-deficient NIK mutants fails to stimulate NF-kappaB and blocks its induction by TNF, by either of the two TNF receptors or by the receptor CD95 (Fas/Apo-1), and by TRADD, RIP and MORT1/FADD, which are adaptor proteins that bind to these receptors. It also blocked NF-kappaB induction by interleukin-1. Our findings indicate that NIK participates in an NF-kappaB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                September 2006
                20 September 2006
                : 43
                : 5
                : 422-436
                Departments of aPathology and bBioengineering, University of Washington, Seattle, Wash., USA
                94884 J Vasc Res 2006;43:422–436
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 8, References: 87, Pages: 15
                Research Paper


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