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 (2008). Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner. Biological chemistry, 389(11), pp. 1399-407. Berlin: Walter de Gruyter 10.1515/BC.2008.160

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Abstract 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-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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea

ISSN:

1431-6730

ISBN:

18783337

Publisher:

Walter de Gruyter

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:03

Last Modified:

23 Oct 2019 12:48

Publisher DOI:

10.1515/BC.2008.160

PubMed ID:

18783337

Web of Science ID:

000262137400007

BORIS DOI:

10.7892/boris.27521

URI:

https://boris.unibe.ch/id/eprint/27521 (FactScience: 108716)

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