Journal
CYTOKINE
Volume 14, Issue 2, Pages 78-87Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1006/cyto.2001.0856
Keywords
c-Fos; c-Jun; IL-6; STAT3; transactivation
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Transcriptional activation of eukaryotic genes often requires the cooperative action of many proteins. The interleukin 6 (IL-6) response element (IRE) is activated by signal transducer and activator of transcription 3 (STAT3), and stimulation with IL-6 leads to STAT3 tyr705 phosphorylation, dimerization, translocation to the nucleus and transactivation of target gene promoters containing IREs, Here, we report that IL-6 and 12-O-tetradecanoylphorbol-13-acetate (TPA) synergistically transactivate the IRE in HepG2 cells, which is coupled to a strong upregulation of c-Jun and c-Fos expression by TPA via the mitogen-activated protein kinase (MAPK) pathway. Overexpression of c-Jun and c-Fos strongly enhanced STAT3-driven IRE transactivation as well as transactivation of the human intercellular adhesion molecule (ICAM)-1 promoter. In contrast, c-Jun mutants lacking the transactivation domain, the DNA-binding domain, or mutants in which the serine residues 63 and 73 were replaced by alanine, did not cooperate with STAT3. In immunoprecipitation experiments, a direct association of STAT3 with c-Jun and c-Fos was observed in response to IL-6, Furthermore, c-Jun/STAT3 and c-Fos/STAT3 complexes were detected on IRE probes in electrophoretic mobility shift assay (EMSA) experiments, but did not bind nor transactivate the TPA response element (TRE), These results demonstrate that activator protein-1 (AP-1) transcription factors can cooperate with STAT3 in IRE transactivation in the absence of direct AP-1 DNA binding. (C) 2001 Academic Press.
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