AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes

EMBO J. 1994 Sep 15;13(18):4370-81.

Abstract

The transcription factor AP-1 contributes significantly to the regulation of interleukin-2 gene transcription during T-cell activation and may play a role in thymocyte development. To study the regulation of AP-1 transcriptional activity in primary T-cells, reporter transgenic mice were generated that express luciferase gene under the control of AP-1 binding sites. Here, we demonstrate that while protein kinase C activation is sufficient to induce DNA-binding activity, an additional intracellular calcium increase is required to induce transcriptional activity of AP-1 in primary mouse T-cells. Furthermore, transcriptional, but not DNA-binding, activity of AP-1 is cyclosporin sensitive and requires tyrosine phosphorylation. This dissociation between DNA-binding and transcriptional activity is likely due, at least partially, to post-translational modifications of the AP-1 complex required for transcriptional activity. Moreover, in addition to these two signals delivered by ligand binding to the T-cell receptor (TcR) AP-1 transcriptional activity absolutely requires the presence of a co-stimulatory signal that can be mediated by the interaction of CD28 with its ligands B7-1 and B7-2. Thus, TcR-mediated and co-stimulatory signals required for T-cell activation appear to be integrated, in part, at the level of the regulation of transcriptional activity of AP-1.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Benzoquinones
  • CD28 Antigens / metabolism
  • Calcium / pharmacology
  • Cyclosporine / pharmacology
  • Ethers, Cyclic / pharmacology
  • Genes, Reporter
  • Interleukin-2 / biosynthesis
  • Lactams, Macrocyclic
  • Lymph Nodes / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Molecular Sequence Data
  • Okadaic Acid
  • Phosphorylation
  • Protein Binding
  • Protein Kinase C / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Quinones / pharmacology
  • Receptors, Antigen, T-Cell / metabolism
  • Rifabutin / analogs & derivatives
  • Signal Transduction*
  • Spleen / cytology
  • T-Lymphocytes / physiology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic* / drug effects

Substances

  • Benzoquinones
  • CD28 Antigens
  • Ethers, Cyclic
  • Interleukin-2
  • Lactams, Macrocyclic
  • Quinones
  • Receptors, Antigen, T-Cell
  • Transcription Factor AP-1
  • Okadaic Acid
  • Rifabutin
  • herbimycin
  • Cyclosporine
  • Protein-Tyrosine Kinases
  • Protein Kinase C
  • Calcium