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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3169-3177.
Prepublished online as a Blood First Edition Paper on January 4, 2005; DOI 10.1182/blood-2004-02-0452.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1–dependent activation of PI-3K/Akt and regulation of Bcl-2 family members

Vidya Limaye, Xiaochun Li, Chris Hahn, Pu Xia, Michael C. Berndt, Mathew A. Vadas, and Jennifer R. Gamble

From the Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, SA, Australia; University of Adelaide, Adelaide, SA, Australia; and Monash University, Melbourne, Australia.

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.


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