Gene interactions and pathways from curated databases and text-mining
J Neurosci 2005, PMID: 16033886

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

Beier, Christoph P; Wischhusen, Jörg; Gleichmann, Marc; Gerhardt, Ellen; Pekanovic, Ana; Krueger, Andreas; Taylor, Verdon; Suter, Ueli; Krammer, Peter H; Endres, Matthias; Weller, Michael; Schulz, Jörg B

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 IkappaB, 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.

Diseases/Pathways annotated by Medline MESH: Glioma, Neuroblastoma
Document information provided by NCBI PubMed

Text Mining Data

caspase-8 → FasL: " The inhibition of PI 3-kinase activity sensitized CGNs to FasL induced caspase-8 and caspase-3 processing and caspase dependent fodrin cleavage "

Manually curated Databases

  • NCI Pathway Database FAS (CD95) signaling pathway: None → PDK1 (PDPK1) (modification, activates)
    Evidence: assay
  • NCI Pathway Database FAS (CD95) signaling pathway: None → AKT1 (AKT1) (modification, activates)
    Evidence: assay
  • NCI Pathway Database FAS (CD95) signaling pathway: PDK1 (PDPK1) → AKT1 (AKT1) (modification, activates)
    Evidence: assay
  • NCI Pathway Database FAS (CD95) signaling pathway: None → None (modification, collaborate)
  • NCI Pathway Database FAS (CD95) signaling pathway: None → PI3K Class IA family (PIK3CA/PIK3R1/PIK3CB/PIK3R1) (modification, collaborate)
  • NCI Pathway Database FAS (CD95) signaling pathway: FASLG/FAS (trimer)/Src/Syk complex (FAS-FASLG-SRC-SYK) → SYK (SYK) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database FAS (CD95) signaling pathway: FASLG/FAS (trimer)/Src/Syk complex (FAS-FASLG-SRC-SYK) → Src (SRC) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database FAS (CD95) signaling pathway: FASLG/FAS (trimer)/Src/Syk complex (FAS-FASLG-SRC-SYK) → FASLG/FAS (trimer) complex (FAS-FASLG) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database FAS (CD95) signaling pathway: SYK (SYK) → Src (SRC) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database FAS (CD95) signaling pathway: SYK (SYK) → FASLG/FAS (trimer) complex (FAS-FASLG) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database FAS (CD95) signaling pathway: Src (SRC) → FASLG/FAS (trimer) complex (FAS-FASLG) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database FAS (CD95) signaling pathway: FASLG/FAS (trimer)/Src/Syk complex (FAS-FASLG-SRC-SYK) → PI3K Class IA family (PIK3CA/PIK3R1/PIK3CB/PIK3R1) (modification, activates)
In total, 23 gene pairs are associated to this article in curated databases