T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression.
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.
Roose
Jeroen P
JP
Department of Medicine, University of California, San Francisco, USA.
Diehn
Maximilian
M
Tomlinson
Michael G
MG
Lin
Joseph
J
Alizadeh
Ash A
AA
Botstein
David
D
Brown
Patrick O
PO
Weiss
Arthur
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001549:Benzamides; D015152:Blotting, Northern; D015153:Blotting, Western; D002469:Cell Separation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D019169:Jurkat Cells; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012313:RNA / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D014443:Tyrosine / Q000737:chemistry
D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008024:Ligands; D010750:Phosphoproteins; D010879:Piperazines; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D014443:Tyrosine; D012313:RNA; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases