title: Early growth response (Egr)-1 gene induction in the thymus in response to TCR ligation during early steps in positive selection is not required for CD8 lineage commitment.
abstract: The early growth response gene 1 (Egr-1) is induced during positive selection in the thymus and has been implicated in the differentiation of CD4+ thymocytes. Here, we show that signals that specifically direct CD8 lineage commitment also induce Egr-1 DNA-binding activity in the nucleus. However, we find that pharmacological inhibition of mitogen-activated protein kinase/extracellular signal-related kinase kinase activity potently inhibits Egr-1 DNA-binding function at concentrations that promote differentiation of CD8+ thymocytes, suggesting Egr-1 activity is not essential for CD8 commitment. To further determine the role of Egr-1 in thymocyte development, we compare steady-state Egr-1 DNA-binding activity in thymocytes from mice with defined defects in positive selection. The data indicate that the appearance of functional Egr-1 is downstream of signals induced by TCR/MHC engagement, whereas it is less sensitive to alterations in Lck-mediated signals, and does not correlate directly with proficient positive selection. Egr-1 is one of the earliest transcription factors induced upon TCR ligation on immature thymocytes, and plays a potential role in the transcription of genes involved in thymocyte selection.
authors.affiliation: Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom.
authors.forename: M A
authors.initials: MA
authors.lastname: Basson
authors.forename: T J
authors.initials: TJ
authors.lastname: Wilson
authors.forename: G A
authors.initials: GA
authors.lastname: Legname
authors.forename: N
authors.initials: N
authors.lastname: Sarner
authors.forename: P D
authors.initials: PD
authors.lastname: Tomlinson
authors.forename: V L
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: R
authors.initials: R
authors.lastname: Zamoyska
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000276:immunology*; D017874:Immediate-Early Proteins; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D018631:ras Proteins / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D018631:ras Proteins