Mitogen-activated protein kinase kinase antagonized fas-associated death domain protein-mediated apoptosis by induced FLICE-inhibitory protein expression

J Exp Med. 1998 Nov 16;188(10):1795-802. doi: 10.1084/jem.188.10.1795.

Abstract

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3- induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Apoptosis / physiology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / metabolism*
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Concanavalin A / pharmacology
  • Fas-Associated Death Domain Protein
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Jurkat Cells
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases*
  • Oligonucleotides, Antisense / pharmacology
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / physiology
  • T-Lymphocytes / metabolism*
  • Transfection / genetics
  • fas Receptor / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Intracellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • Receptors, Tumor Necrosis Factor
  • fas Receptor
  • Concanavalin A
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases