The GABP-responsive Element of the Interleukin-2 Enhancer Is Regulated by JNK/SAPK-activating Pathways in T Lymphocytes

• Published in: The Journal of biological chemistry 1998-04, Vol.273 (17), p.10112-10119
• Main Authors: Hoffmeyer, Angelika, Avots, Andris, Flory, Egbert, Weber, Christoph K., Serfling, Edgar, Rapp, Ulf R.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic; Enzyme Activation; GA-Binding Protein Transcription Factor; Humans; Interleukin-2 - genetics; Ionomycin - pharmacology; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinases; Mice; Mitogen-Activated Protein Kinase Kinase Kinase 11; Mitogen-Activated Protein Kinases; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; T-Lymphocytes - enzymology; Transcription Factors - metabolism; Transcription, Genetic; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.17.10112

T cell activation leads via multiple intracellular signaling pathways to rapid induction of interleukin-2 (IL-2) expression, which can be mimicked by costimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. We have identified a distal IL-2 enhancer regulated by the Raf-MEK-ERK signaling pathway, which can be induced by TPA/ionomycin treatment. It contains a dyad symmetry element (DSE) controlled by the Ets-like transcription factor GA-binding protein (GABP), a target of activated ERK. TPA/ionomycin treatment of T cells stimulates both mitogen-activated ERK, as well as the stress-activated mitogen-activated protein kinase family members JNK/SAPK and p38. In this study, we investigated the contribution of the stress-activated pathways to the induction of the distal IL-2 enhancer. We show that JNK- but not p38-activating pathways regulate the DSE activity. Furthermore, the JNK/SAPK signaling pathway cooperates with the Raf-MEK-ERK cascade in TPA/ionomycin-induced DSE activity. In T cells, overexpression of SPRK/MLK3, an activator of JNK/SAPK, strongly induces DSE-dependent transcription and dominant negative kinases of SEK and SAPK impair TPA/ionomycin-induced DSE activity. Blocking both ERK and JNK/SAPK pathways abolishes the DSE induction. The inducibility of the DSE is strongly dependent on the Ets-core motifs, which are bound by GABP. Both subunits of GABP are phosphorylated upon JNK activation in vivo and three different isoforms of JNK/SAPK, but not p38, in vitro. Our data suggest that GABP is targeted by signaling events from both ERK and JNK/SAPK pathways. GABP therefore is a candidate for signal integration and regulation of IL-2 transcription in T lymphocytes.