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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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B-Lymphocytes / metabolism
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Benzamides
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Blotting, Northern
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Blotting, Western
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Cell Separation
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DNA, Complementary / metabolism
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DNA-Binding Proteins / metabolism
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / physiology*
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Flow Cytometry
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Gene Expression Regulation*
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Homeodomain Proteins / metabolism*
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Humans
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Imatinib Mesylate
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Immunoprecipitation
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Jurkat Cells
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Ligands
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MAP Kinase Signaling System
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Mice
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Models, Biological
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Molecular Sequence Data
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Multigene Family
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Oligonucleotide Array Sequence Analysis
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Phosphoproteins / metabolism
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Phosphorylation
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Piperazines / pharmacology
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins c-abl / physiology*
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Pyrimidines / pharmacology
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RNA / chemistry
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Receptors, Antigen, T-Cell / physiology*
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Signal Transduction
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Thymus Gland / cytology
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Thymus Gland / metabolism
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Thymus Gland / pathology
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Transcription, Genetic
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Tyrosine / chemistry
Substances
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Adaptor Proteins, Signal Transducing
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Benzamides
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DNA, Complementary
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DNA-Binding Proteins
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Homeodomain Proteins
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Ligands
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Phosphoproteins
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Piperazines
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Pyrimidines
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Receptors, Antigen, T-Cell
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SLP-76 signal Transducing adaptor proteins
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V(D)J recombination activating protein 2
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RAG-1 protein
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Tyrosine
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RNA
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Imatinib Mesylate
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Proto-Oncogene Proteins c-abl
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Protein Kinase C
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Extracellular Signal-Regulated MAP Kinases