PMID- 16033886
OWN - NLM
STAT- MEDLINE
DCOM- 20060215
LR  - 20201209
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 25
IP  - 29
DP  - 2005 Jul 20
TI  - FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 
      3-kinase-Akt/protein kinase B-dependent expression of lifeguard/neuronal membrane 
      protein 35.
PG  - 6765-74
AB  - 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.
FAU - Beier, Christoph P
AU  - Beier CP
AD  - Department of Neurology, Medical School, University of Tubingen, 72076 Tubingen, 
      Germany.
FAU - Wischhusen, Jorg
AU  - Wischhusen J
FAU - Gleichmann, Marc
AU  - Gleichmann M
FAU - Gerhardt, Ellen
AU  - Gerhardt E
FAU - Pekanovic, Ana
AU  - Pekanovic A
FAU - Krueger, Andreas
AU  - Krueger A
FAU - Taylor, Verdon
AU  - Taylor V
FAU - Suter, Ueli
AU  - Suter U
FAU - Krammer, Peter H
AU  - Krammer PH
FAU - Endres, Matthias
AU  - Endres M
FAU - Weller, Michael
AU  - Weller M
FAU - Schulz, Jorg B
AU  - Schulz JB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Faim2 protein, rat)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Fasl protein, mouse)
RN  - 0 (Faslg protein, rat)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Necrosis Factors)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Casp8 protein, mouse)
RN  - EC 3.4.22.- (Casp8 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 8)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - Apoptosis/*physiology
MH  - Caspase 3
MH  - Caspase 8
MH  - Caspases/metabolism
MH  - Cell Differentiation
MH  - Cell Line, Tumor
MH  - Cells, Cultured
MH  - Cerebellum/cytology
MH  - Fas Ligand Protein
MH  - Gene Expression Regulation/physiology
MH  - Glioma
MH  - Membrane Glycoproteins/genetics/*metabolism
MH  - Mice
MH  - Nerve Tissue Proteins/*genetics/metabolism
MH  - Neuroblastoma
MH  - Neurons/*cytology/physiology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Promoter Regions, Genetic/physiology
MH  - RNA, Small Interfering
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Transfection
MH  - Tumor Necrosis Factors/genetics/*metabolism
PMC - PMC6725360
EDAT- 2005/07/22 09:00
MHDA- 2006/02/16 09:00
PMCR- 2006/01/20
CRDT- 2005/07/22 09:00
PHST- 2005/07/22 09:00 [pubmed]
PHST- 2006/02/16 09:00 [medline]
PHST- 2005/07/22 09:00 [entrez]
PHST- 2006/01/20 00:00 [pmc-release]
AID - 25/29/6765 [pii]
AID - 10.1523/JNEUROSCI.1700-05.2005 [doi]
PST - ppublish
SO  - J Neurosci. 2005 Jul 20;25(29):6765-74. doi: 10.1523/JNEUROSCI.1700-05.2005.