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T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression.

  • Author(s): Roose, Jeroen P;
  • Diehn, Maximilian;
  • Tomlinson, Michael G;
  • Lin, Joseph;
  • Alizadeh, Ash A;
  • Botstein, David;
  • Brown, Patrick O;
  • Weiss, Arthur
  • Editor(s): Philippa Marrack
  • et al.
Abstract

Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligand-independent signaling by the precursors of mature antigen receptors regulates development of B and T lymphocytes. Here we describe a basal signal that controls gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG-2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results in constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or inhibition of signaling events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation.

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