c-Jun NH2-terminal kinase activation leads to a FADD-dependent but Fas ligand-independent cell death in Jurkat T cells

J Biol Chem. 2001 Mar 16;276(11):8350-7. doi: 10.1074/jbc.M008431200. Epub 2000 Dec 5.

Abstract

Persistent c-Jun NH2-terminal kinase (JNK) activation induces cell death. Different mechanisms are ascribed to JNK-induced cell death. Most of the JNK-apoptosis studies employ stress stimuli known to activate kinases other than JNK. Here we used overexpression of mitogen-activated protein kinase kinase 7 (MKK7) to activate selectively JNK in T lymphoma Jurkat cells. Similar to that reported previously, Fas ligand (FasL) expression was up-regulated by JNK activation. Dominant negative-FADD and caspase-8 inhibitor benzyloxycarbonyl-Ile-Glu-Thr-Asp effectively inhibited MKK7-induced cell death, supporting a major involvement of FADD cascade. However, MKK7-induced cell death was not prevented by antagonist antibody ZB4 and Fas-Fc, indicating that Fas-FasL interaction is minimally involved. Confocal microscopy revealed that persistent JNK activation led to clustering of Fas. Our results suggest that, in contrast to that reported previously, JNK alone-induced death in Jurkat cells is FADD-dependent but is not triggered by Fas-FasL interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Apoptosis*
  • Carrier Proteins / physiology*
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Enzyme Activation
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells
  • MAP Kinase Kinase 7
  • MAP Kinase Kinase Kinase 1*
  • Membrane Glycoproteins / physiology*
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Mitogen-Activated Protein Kinases / physiology*
  • Protein Serine-Threonine Kinases / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Caspase Inhibitors
  • FADD protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Membrane Glycoproteins
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • MAP Kinase Kinase 7
  • MAP2K7 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9