Document Detail


Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner.
MedLine Citation:
PMID:  18783337     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Lotte P Hofmann; Shuyu Ren; Stephanie Schwalm; Josef Pfeilschifter; Andrea Huwiler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biological chemistry     Volume:  389     ISSN:  1431-6730     ISO Abbreviation:  Biol. Chem.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-18     Completed Date:  2008-12-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9700112     Medline TA:  Biol Chem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1399-407     Citation Subset:  IM    
Affiliation:
Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / genetics
Gene Expression Regulation / drug effects
Mesangial Cells / cytology*,  drug effects,  enzymology*
Mice
Mice, Knockout
Phosphotransferases (Alcohol Group Acceptor) / deficiency,  metabolism*
Signal Transduction / drug effects
Staurosporine / pharmacology
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 62996-74-1/Staurosporine; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase

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