Slow accumulation of active mitogen-activated protein kinase during thymocyte differentiation regulates the temporal pattern of transcription factor gene expression.
Thymocyte-positive selection is believed to result from low affinity/avidity interactions of TCR and MHC proteins, but how these weak interactions translate into downstream biochemical signals and how such signals modulate gene expression is unknown. Using a culture system where isolated immature thymocytes can be induced to differentiate along the CD4 lineage pathway, we show that sustained low level mitogen-activated protein/extracellular regulated kinase activity is required for cell differentiation and survival. Furthermore, induction of mitogen-activated protein/extracellular regulated kinase activity is surprisingly slow under conditions that induce differentiation. This pattern of kinase activity not only selects which genes are expressed but also regulates the temporal pattern of expression of transcription factor genes that are induced during double-positive thymocyte differentiation.
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
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Shao
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Wilkinson
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Lee
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Han
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Kaye
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D017874:Immediate-Early Proteins; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases