Induction of the early growth response gene 1 promoter by TCR agonists and partial agonists: ligand potency is related to sustained phosphorylation of extracellular signal-related kinase substrates.
Responses to partial agonist TCR signals include positive selection of thymocytes, survival of naive T cells, and homeostatic proliferation. As part of an effort to understand the molecular basis of these processes, we have determined how agonist and partial agonist ligands act differently to induce a change in gene expression. We have found that the early growth response gene 1 (Egr1) promoter is activated by agonist and partial agonist ligands, but the partial agonist induces 10-fold lower promoter activity. Both agonist and partial agonist ligands require all six serum response elements in the Egr1 promoter to reach maximum induction. Although slightly fewer cells respond to the partial agonist, all of the responding cells have reduced activity compared with the cells responding to agonist. The factors binding to the serum response elements of the Egr1 promoter form a ternary complex (TC) consisting of serum response factor and either Elk-1 or serum response factor accessory protein-1a. Formation of a stable TC and inducible promoter activity are both dependent on extracellular signal-related kinase activation. Examination of TC formation over time reveals that this complex is induced well by partial agonist ligands, but it is not sustained, whereas agonist stimulation induces longer lived TCs. Therefore, the data suggest that both agonist and partial agonist ligands can induce formation of multiple TC on the Egr1 promoter, but the ability of the agonist ligand to maintain these complexes for an extended time results in the increased potency of the agonist.
Xi
Hongkang
H
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kersh
Gilbert J
GJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D017874:Immediate-Early Proteins; D008024:Ligands; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000502:physiology*; D027602:Serum Response Element / Q000276:immunology; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013379:Substrate Specificity / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C494113:Elk1 protein, mouse; C494194:Elk4 protein, mouse; D017874:Immediate-Early Proteins; D008024:Ligands; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011948:Receptors, Antigen, T-Cell; D026362:Serum Response Factor; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases