FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-akt/protein kinase B-dependent expression of lifeguard/neuronal membrane protein 35

• Verfasst von: Beier, Christoph-Patrick [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Titel: FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-akt/protein kinase B-dependent expression of lifeguard/neuronal membrane protein 35
• Verf.angabe: 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
• E-Jahr: 2005
• Jahr: 20 July 2005
• Umfang: 10 S.
• Teil: volume:25
• Teil: year:2005
• Teil: number:29
• Teil: day:20
• Teil: month:07
• Teil: pages:6765-6774
• Teil: extent:10
• Fussnoten: Gesehen am 04.03.2021
• Titel Quelle: Enthalten in: The journal of neuroscience
• Ort Quelle: Washington, DC : Soc., 1981
• Jahr Quelle: 2005
• Band/Heft Quelle: 25(2005), 29 vom: 20. Juli, Seite 6765-6774
• ISSN Quelle: 1529-2401
• DOI: doi:10.1523/JNEUROSCI.1700-05.2005
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: apoptosis
• Sach-SW: caspase
• Sach-SW: cerebellar granule neurons
• Sach-SW: Fas/CD95
• Sach-SW: lifeguard
• Sach-SW: PI 3-kinase/Akt
• K10plus-PPN: 1750427923

Abstract

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.