Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases

Cell Death Differ. 1998 Jan;5(1):29-37. doi: 10.1038/sj.cdd.4400307.

Abstract

Fas/CD95/Apo-I has been shown to stimulate a variety of molecules including several members of the caspase family and the acidic sphingomyelinase (Martin and Green 1995; Gulbins et al, 1995). Here, we demonstrate that Fas receptor-triggered activation of the acidic sphingomyelinase, consumption of sphingomyelin, release of ceramide, and subsequent activation of JNK and p38-K are regulated by caspases. Inhibition of caspases by Ac-YVAD-chloromethylketone or transient CrmA transfection prevented stimulation of acidic sphingomyelinase, release of ceramide and activation of JNK and p38-K upon Fas-receptor crosslinking. Likewise, Fas triggered apoptosis was almost completely blocked by Ac-YVAD-chloromethylketone or CrmA mediated inhibition of caspases. The results suggest a new signalling cascade from the Fas receptor via caspases to acidic sphingomyelinase, ceramide and JNK/p38-K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / metabolism
  • Adrenergic Uptake Inhibitors / pharmacology
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Caspases / metabolism*
  • Ceramides / metabolism
  • Cysteine Proteinase Inhibitors / genetics
  • Cysteine Proteinase Inhibitors / pharmacology
  • Diglycerides / metabolism
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Imipramine / pharmacology
  • Jurkat Cells / cytology*
  • Jurkat Cells / enzymology
  • Mitogen-Activated Protein Kinases*
  • Serpins / genetics
  • Signal Transduction / physiology
  • Sphingomyelin Phosphodiesterase / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / enzymology
  • Transfection
  • Viral Proteins*
  • fas Receptor / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Acids
  • Adrenergic Uptake Inhibitors
  • Amino Acid Chloromethyl Ketones
  • Ceramides
  • Cysteine Proteinase Inhibitors
  • Diglycerides
  • N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
  • Serpins
  • Viral Proteins
  • fas Receptor
  • interleukin-1beta-converting enzyme inhibitor
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Sphingomyelin Phosphodiesterase
  • Caspases
  • Imipramine