Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter

Mol Cell Biol. 1998 Sep;18(9):5414-24. doi: 10.1128/MCB.18.9.5414.

Abstract

T lymphocytes undergo apoptosis in response to a variety of stimuli, including exposure to UV radiation and gamma-irradiation. While the mechanism by which stress stimuli induce apoptosis is not well understood, we have previously shown that the induction of Fas ligand (FasL) gene expression by environmental stress stimuli is dependent on c-Jun N-terminal kinase (JNK) activation. Using inducible dominant-active (DA) JNK kinase kinase (MEKK1) expression in Jurkat cells, we map a specific MEKK1-regulated response element to positions -338 to -316 of the Fas ligand (FasL) promoter. Mutation of that response element abrogated MEKK1-mediated FasL promoter activation and interfered in stress-induced activation of that promoter. Using electrophoretic mobility shift assays, we demonstrate that activator protein 1 (AP-1) binding proteins, namely, activating transcription factor 2 (ATF2) and c-Jun, bind to the MEKK1 response element. Transient transfection of interfering c-Jun and ATF2 mutants, which lack the consensus JNK phosphorylation sites, abrogated the transcriptional activation of the FasL promoter, demonstrating the involvement of these transcription factors in the regulation of the FasL promoter. Taken together, our data indicate that MEKK1 and transcription factors regulated by the JNK pathway play a role in committing lymphocytes to undergo apoptosis by inducing FasL expression via a novel response element in the promoter of that gene.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Binding Sites
  • Consensus Sequence
  • Cytokines / pharmacology*
  • Enzyme Activation
  • Enzyme Induction
  • Fas Ligand Protein
  • Gamma Rays
  • Genes, Reporter
  • Humans
  • Jurkat Cells / drug effects
  • Jurkat Cells / physiology
  • Jurkat Cells / radiation effects
  • Luciferases / biosynthesis
  • MAP Kinase Kinase Kinase 1*
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics*
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic*
  • Protein Serine-Threonine Kinases / biosynthesis
  • Protein Serine-Threonine Kinases / metabolism*
  • Recombinant Fusion Proteins / biosynthesis
  • Sequence Deletion
  • Stress, Physiological
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology*
  • T-Lymphocytes / radiation effects
  • Transfection
  • Ultraviolet Rays

Substances

  • Cytokines
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • Luciferases
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human