The control of the balance between ceramide and sphingosine-1-phosphate by sphingosine kinase: Oxidative stress and the seesaw of cell survival and death

2012 ◽  
Vol 163 (1) ◽  
pp. 26-36 ◽  
Author(s):  
James R. Van Brocklyn ◽  
Joseph B. Williams
Keyword(s):  
Oxidative Stress ◽  
Cell Survival ◽  
Sphingosine Kinase ◽  
Sphingosine 1 Phosphate

scholarly journals A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection

2011 ◽  
Vol 106 (6) ◽  
pp. 1341-1353 ◽  
Author(s):  
Ludovic Gomez ◽  
Melanie Paillard ◽  
Megan Price ◽  
Qun Chen ◽  
Geoffrey Teixeira ◽  
...  
Keyword(s):  
Cell Survival ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate

scholarly journals Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate

2011 ◽  
Vol 440 (3) ◽  
pp. 345-353 ◽  
Author(s):  
Yugesh Kharel ◽  
Thomas P. Mathews ◽  
Amanda M. Gellett ◽  
Jose L. Tomsig ◽  
Perry C. Kennedy ◽  
...  
Keyword(s):  
Cell Survival ◽  
Sphingosine Kinase ◽  
Rapid Onset ◽  
Physiological Functions ◽  
Extracellular Signal ◽  
Signalling Molecule ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration

S1P (sphingosine 1-phosphate) is a signalling molecule involved in a host of cellular and physiological functions, most notably cell survival and migration. S1P, which signals via a set of five G-protein-coupled receptors (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases) from Sph (sphingosine). Interfering RNA strategies and SphK1 (sphingosine kinase type 1)-null (Sphk1−/−) mouse studies implicate SphK1 in multiple signalling cascades, yet there is a paucity of potent and selective SphK1 inhibitors necessary to evaluate the effects of rapid onset inhibition of this enzyme. We have identified a set of submicromolar amidine-based SphK1 inhibitors and report using a pair of these compounds to probe the cellular and physiological functions of SphK1. In so doing, we demonstrate that our inhibitors effectively lower S1P levels in cell-based assays, but we have been unable to correlate SphK1 inhibition with changes in cell survival. However, SphK1 inhibition did diminish EGF (epidermal growth factor)-driven increases in S1P levels and Akt (also known as protein kinase B)/ERK (extracellular-signal-regulated kinase) phosphorylation. Finally, administration of the SphK1 inhibitor to wild-type, but not Sphk1−/−, mice resulted in a rapid decrease in blood S1P levels indicating that circulating S1P is rapidly turned over.

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

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3169-3177 ◽  
Author(s):  
Vidya Limaye ◽  
Xiaochun Li ◽  
Chris Hahn ◽  
Pu Xia ◽  
Michael C. Berndt ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Protein Kinase ◽  
Cell Survival ◽  
Phosphatidyl Inositol ◽  
B Cell Lymphoma ◽  
Sphingosine Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate

AbstractSphingosine-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.

scholarly journals Fingolimod attenuates renal ischemia/reperfusion-induced acute lung injury by inhibiting inflammation and apoptosis and modulating S1P metabolism

2021 ◽  
Vol 49 (8) ◽  
pp. 030006052110328
Author(s):  
Zu-an Shi ◽  
Ting-ting Li ◽  
Dao-ling Kang ◽  
Hang Su ◽  
Fa-ping Tu
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Pulmonary Inflammation ◽  
Sphingosine Kinase ◽  
Renal Ischemia ◽  
Cytokine Levels ◽  
Sphingosine 1 Phosphate

Objective This study examined whether the immunomodulator fingolimod (FTY720) could alleviate renal ischemia/reperfusion (I/R)-induced lung injury and explored the potential mechanisms. Methods Renal I/R was established in a rat model, and FTY720 (0.5, 1, or 2 mg/kg) was injected intraperitoneally after 15 minutes of ischemia. Pro-inflammatory cytokine levels, oxidative stress, apoptosis, and the mRNA expression of the sphingosine-1-phosphate (S1P)-related signaling pathway genes sphingosine kinase-1 (SphK1) and sphingosine kinase-2 were analyzed in lung tissue. Results Increased pro-inflammatory cytokine levels; decreased total superoxide dismutase, catalase, and glutathione peroxidase levels; increased apoptosis; and increased S1P lyase and SphK1 expression were observed following renal I/R. FTY720 reversed renal I/R-induced changes and effectively attenuated lung injury. Conclusion FTY720 protected against acute lung injury in rats subjected to renal I/R by decreasing pulmonary inflammation and apoptosis, increasing oxidative stress, and modulating S1P metabolism.

Apoptotic cell extrusion depends on single-cell synthesis of sphingosine-1-phosphate by sphingosine kinase 2

2021 ◽  
Vol 1866 (4) ◽  
pp. 158888
Author(s):  
Bruno Jaime Santacreu ◽  
Daniela Judith Romero ◽  
Lucila Gisele Pescio ◽  
Estefanía Tarallo ◽  
Norma Beatriz Sterin-Speziale ◽  
...  
Keyword(s):  
Single Cell ◽  
Apoptotic Cell ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Cell Synthesis ◽  
Cell Extrusion

scholarly journals Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

2004 ◽  
Vol 279 (50) ◽  
pp. 52487-52492 ◽  
Author(s):  
Maria L. Allende ◽  
Teiji Sasaki ◽  
Hiromichi Kawai ◽  
Ana Olivera ◽  
Yide Mi ◽  
...  
Keyword(s):  
Vascular Development ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Cellular Functions ◽  
Lymphocyte Trafficking ◽  
Signaling Molecule ◽  
Physiological Functions ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

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