QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 20, 2005, 25(29):6765-6774; doi:10.1523/JNEUROSCI.1700-05.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Beier, C. P. Articles by Schulz, J. B. Search for Related Content PubMed PubMed Citation Articles by Beier, C. P. Articles by Schulz, J. B.

 Previous Article  |  Next Article 

Neurobiology of Disease
FasL (CD95L/APO-1L) Resistance of Neurons Mediated by Phosphatidylinositol 3-Kinase-Akt/Protein Kinase B-Dependent Expression of Lifeguard/Neuronal Membrane Protein 35

Christoph P. Beier,¹ Jörg Wischhusen,² Marc Gleichmann,¹ Ellen Gerhardt,^1,3 Ana Pekanovic,^1,3 Andreas Krueger,⁴ Verdon Taylor,⁵ Ueli Suter,⁵ Peter H. Krammer,⁴ Matthias Endres,⁶ Michael Weller,² and Jörg B. Schulz^1,3

Laboratories of ¹Neurodegeneration and ²Molecular Neurooncology, Department of Neurology, Medical School, University of Tübingen, 72076 Tübingen, Germany, ³Department of Neurodegeneration and Restorative Research, Center of Molecular Physiology of the Brain and Center of Neurological Medicine, University of Göttingen, 37073 Göttingen, Germany, ⁴Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany, ⁵Institute of Cell Biology, Department of Biology, Eidgenössische Technische Hochschule, 8093 Zürich, Switzerland, and ⁶Department of Neurology, Charité, Humboldt University, 10117 Berlin, Germany

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 IB, 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.

Key words: apoptosis; Fas/CD95; lifeguard; cerebellar granule neurons; PI 3-kinase/Akt; caspase

---

Received Dec 30, 2004; revised June 1, 2005; accepted June 1, 2005.

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help