Please use this identifier to cite or link to this item: 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
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