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https://hdl.handle.net/2440/17469
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Type: | Journal article |
Title: | Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members |
Author: | Limaye, V. Li, X. Hahn, C. Xia, P. Berndt, M. Vadas, M. Gamble, J. |
Citation: | Blood, 2005; 105(8):3169-3177 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2005 |
ISSN: | 0006-4971 1528-0020 |
Abstract: | Sphingosine-1-phosphate (S1P), the bioactive product of sphingosine kinase (SK) activation, is a survival factor for endothelial cells. The mechanism of SK-mediated survival was investigated in endothelial cells with moderately raised intracellular SK activity. Overexpression of SK mediated survival primarily through the activation of the phosphatidyl inositol 3-kinase (PI-3K)/protein kinase B (Akt/PKB) pathway and an associated up-regulation of the antiapoptotic protein B cell lymphoma gene 2 (Bcl-2) and down-regulation of the proapoptotic protein bisindolylmaleimide (Bcl-2 interacting mediator of cell death; Bim). In addition there was an up-regulation and dephosphorylation of the junctional molecule platelet endothelial cell adhesion molecule-1 (PECAM-1), which was obligatory for activation of the PI-3K/Akt pathway, for SK-induced cell survival, and for the changes in the apoptosis-related proteins. Thus, raised intracellular SK activity induced a molecule involved in cell-cell interactions to augment cell survival through a PI-3K/Akt-dependent pathway. This is distinct from the activation of both PI-3K/Akt and mitogen-activated protein kinase (MAPK) pathways seen with exogenously added S1P. Cells overexpressing SK showed enhanced survival under conditions of serum deprivation and absence of attachment to extracellular matrix, suggesting a role for SK in the regulation of vascular phenomena that occur under conditions of stress, such as angiogenesis and survival in unattached states, as would be required for a circulating endothelial cell. |
Keywords: | Endothelium, Vascular Umbilical Veins Cells, Cultured Humans Phosphotransferases (Alcohol Group Acceptor) Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Culture Media, Serum-Free Signal Transduction Apoptosis Cell Survival Gene Expression Regulation, Enzymologic Phosphorylation Neovascularization, Physiologic Proto-Oncogene Proteins c-akt Phosphatidylinositol 3-Kinases Platelet Endothelial Cell Adhesion Molecule-1 Protein Serine-Threonine Kinases |
DOI: | 10.1182/blood-2004-02-0452 |
Published version: | http://dx.doi.org/10.1182/blood-2004-02-0452 |
Appears in Collections: | Aurora harvest 6 Medicine publications |
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