PMID- 9492297
OWN - NLM
STAT- MEDLINE
DCOM- 19980323
LR  - 20190620
IS  - 0014-2956 (Print)
IS  - 0014-2956 (Linking)
VI  - 251
IP  - 1-2
DP  - 1998 Jan 15
TI  - Role of an acidic compartment in tumor-necrosis-factor-alpha-induced production 
      of ceramide, activation of caspase-3 and apoptosis.
PG  - 295-303
AB  - Tumor necrosis factor-alpha (TNF-alpha) apoptosis by recruiting a complex of 
      cytosolic proteins at its plasma membrane receptor. Among them is caspase-8, an 
      interleukin-1beta-converting enzyme (ICE)-like protease that initiates an 
      amplified protease cascade to activate the cell-death machinery. The latter 
      comprises at least caspase-3 and caspase-7, which execute cell death by cleaving 
      numerous protein substrates, including poly(ADP-ribose) polymerase. In addition, 
      TNF-alpha stimulates the production of ceramide, which also activates the death 
      machinery. Whether the signaling pathways elicited by caspase-8 and ceramide 
      proceed independently or intersect at a specific subcellular site is unknown. 
      Using the lysosomotropic agent NH4Cl and the vesicularization inhibitor brefeldin 
      A, we show here the convergence of TNF-alpha-induced death signaling on an 
      acidic, subcellular compartment reminiscent of lysosomes. This compartment 
      generates at least two signaling pathways that account for the caspase-3 
      activation and apoptosis induced by TNF-alpha, one involving ceramide and 
      caspase-unrelated adapter molecules and another involving yet unknown lysosomal 
      mediators. The apoptosis inhibitor Bcl-2 specifically acts on the 
      ceramide-activated pathway to block caspase-3 activation and apoptosis. The 
      latter result explains why Bcl-2 only partially blocks TNF-alpha-induced 
      apoptosis.
FAU - Monney, L
AU  - Monney L
AD  - Institute of Biochemistry, University of Fribourg, Switzerland.
FAU - Olivier, R
AU  - Olivier R
FAU - Otter, I
AU  - Otter I
FAU - Jansen, B
AU  - Jansen B
FAU - Poirier, G G
AU  - Poirier GG
FAU - Borner, C
AU  - Borner C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Eur J Biochem
JT  - European journal of biochemistry
JID - 0107600
RN  - 0 (Cyclopentanes)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (N-acetylsphingosine)
RN  - 0 (Oligopeptides)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (benzyloxycarbonyl-valyl-alanyl-aspartyl-fluoromethane)
RN  - 01Q9PC255D (Ammonium Chloride)
RN  - 20350-15-6 (Brefeldin A)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Ammonium Chloride/pharmacology
MH  - Animals
MH  - Apoptosis/*drug effects/physiology
MH  - Brefeldin A
MH  - Caspase 3
MH  - *Caspases
MH  - Cell Compartmentation/*drug effects
MH  - Cyclopentanes/pharmacology
MH  - Cysteine Endopeptidases/drug effects/*metabolism
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Endosomes/metabolism
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - Lysosomes/metabolism
MH  - Mice
MH  - Oligopeptides/pharmacology
MH  - Poly(ADP-ribose) Polymerases/drug effects/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Signal Transduction
MH  - Sphingomyelin Phosphodiesterase/metabolism
MH  - Sphingosine/*analogs & derivatives/metabolism/pharmacology
MH  - Tumor Necrosis Factor-alpha/metabolism/*pharmacology
EDAT- 1998/03/10 00:00
MHDA- 1998/03/10 00:01
CRDT- 1998/03/10 00:00
PHST- 1998/03/10 00:00 [pubmed]
PHST- 1998/03/10 00:01 [medline]
PHST- 1998/03/10 00:00 [entrez]
AID - 10.1046/j.1432-1327.1998.2510295.x [doi]
PST - ppublish
SO  - Eur J Biochem. 1998 Jan 15;251(1-2):295-303. doi: 
      10.1046/j.1432-1327.1998.2510295.x.