Fulltext

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

Hofmann, Lotte P. ; Ren, Shuyu ; Schwalm, Stephanie ; Pfeilschifter, Josef ; Huwiler, Andrea

In: Biological Chemistry, 2008, vol. 389, no. 11, p. 1399-1407

Ajouter à la liste personnelle
    Titre
    • Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner
    Auteur
    • Hofmann, Lotte P.. Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland and Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
    • Ren, Shuyu. Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland
    • Schwalm, Stephanie. Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland and Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
    • Pfeilschifter, Josef. Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
    • Huwiler, Andrea. Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Biological Chemistry, 2008, vol. 389, no. 11, p. 1399-1407. Walter de Gruyter
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:302788
    Summary
    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. Wild-type 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 highly 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-XL 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-XL expression. Thus, subtype-selective targeting of SKs will be critical when considering these enzymes as therapeutic targets for the treatment of inflammation or cancer