FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-akt/protein kinase B-dependent expression of lifeguard/neuronal membrane protein 35
The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was medi...
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| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
20 July 2005
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| In: |
The journal of neuroscience
Year: 2005, Jahrgang: 25, Heft: 29, Pages: 6765-6774 |
| ISSN: | 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.1700-05.2005 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1523/JNEUROSCI.1700-05.2005 Verlag, lizenzpflichtig, Volltext: https://www.jneurosci.org/content/25/29/6765 
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| Verfasserangaben: | Christoph P. Beier, Jörg Wischhusen, Marc Gleichmann, Ellen Gerhardt, Ana Pekanovic, Andreas Krueger, Verdon Taylor, Ueli Suter, Peter H. Krammer, Matthias Endres, Michael Weller, and Jörg B. Schulz |
| Zusammenfassung: | The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI 3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI 3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI 3-kinase, overexpression of the inhibitory protein IκB, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI 3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e.g., inhibition of the PI 3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL. |
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| Beschreibung: | Gesehen am 04.03.2021 |
| Beschreibung: | Online Resource |
| ISSN: | 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.1700-05.2005 |