AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes.
The transcription factor AP-1 contributes significantly to the regulation of interleukin-2 gene transcription during T-cell activation and may play a role in thymocyte development. To study the regulation of AP-1 transcriptional activity in primary T-cells, reporter transgenic mice were generated that express luciferase gene under the control of AP-1 binding sites. Here, we demonstrate that while protein kinase C activation is sufficient to induce DNA-binding activity, an additional intracellular calcium increase is required to induce transcriptional activity of AP-1 in primary mouse T-cells. Furthermore, transcriptional, but not DNA-binding, activity of AP-1 is cyclosporin sensitive and requires tyrosine phosphorylation. This dissociation between DNA-binding and transcriptional activity is likely due, at least partially, to post-translational modifications of the AP-1 complex required for transcriptional activity. Moreover, in addition to these two signals delivered by ligand binding to the T-cell receptor (TcR) AP-1 transcriptional activity absolutely requires the presence of a co-stimulatory signal that can be mediated by the interaction of CD28 with its ligands B7-1 and B7-2. Thus, TcR-mediated and co-stimulatory signals required for T-cell activation appear to be integrated, in part, at the level of the regulation of transcriptional activity of AP-1.
Rincón
M
M
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
Flavell
R A
RA
D000818:Animals; D001483:Base Sequence; D016227:Benzoquinones; D018106:CD28 Antigens / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology; D017930:Genes, Reporter; D007376:Interleukin-2 / Q000096:biosynthesis; D047029:Lactams, Macrocyclic; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019319:Okadaic Acid; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D016227:Benzoquinones; D018106:CD28 Antigens; D004988:Ethers, Cyclic; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D011809:Quinones; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D019319:Okadaic Acid; D017828:Rifabutin; C020754:herbimycin; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium