Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

Lotte P. Hofmann, Shuyu Ren, Stephanie Schwalm, Josef Pfeilschifter, Andrea Huwiler
2008 Biological chemistry  
Sphingosine kinases (SKs) are key enzymes regulating the production of sphingosine-1-phosphate (S1P), which determines important cell responses including cell growth and death. Here we show that renal mesangial cells isolated from wild-type, SK-1 -/-, and SK-2 -/-mice show a differential response to apoptotic stimuli. Wildtype mesangial cells responded to staurosporine with increased DNA fragmentation and caspase-3 processing, which was enhanced in SK-1 -/-cells. In contrast, SK-2 -/cells were
more » ... ighly resistant to staurosporine-induced apoptosis. Furthermore, the basal phosphorylation and activity of the anti-apoptotic protein kinase B (PKB) and of its substrate Bad were decreased in SK-1 -/-but not in SK-2 -/-cells. Upon staurosporine treatment, phosphorylation of PKB and Bad decreased in wild-type and SK-1 -/-cells, but remained high in SK-2 -/-cells. In addition, the anti-apoptotic Bcl-X L was significantly upregulated in SK-2 -/-cells, which may further contribute to the protective state of these cells. In summary, our data show that SK-1 and SK-2 have opposite effects on the capacity of mesangial cells to resist apoptotic stimuli. This is due to differential modulation of the PKB/Bad pathway and of Bcl-X L expression. Thus, subtype-selective targeting of SKs will be critical when considering these enzymes as therapeutic targets for the treatment of inflammation or cancer.
doi:10.1515/bc.2008.160 pmid:18783337 fatcat:zxydzdhkxja4nfasis4brra25m