Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein.
STAT3 (signal transducer and activator of transcription 3) is a key transcription factor mediating the signals for a variety of cytokines, including interleukin-6 (IL-6). The Stat3 gene itself is activated by IL-6 signals. We show that the region of the signal-transducing subunit, gp130, essential for STAT3 activation, is also required for activation of the Stat3 gene. To elucidate the mechanisms activating the Stat3 gene, we identified an IL-6 response element (IL-6RE) in the Stat3 gene promoter containing both a low affinity STAT3-binding element and a cAMP-responsive element (CRE). Electrophoretic mobility shift assays showed that IL-6 induced a slowly migrating complex on the IL-6RE containing a STAT3 homodimer and an unidentified CRE-binding protein. With the combination of transient transfection assays using mutant Stat3 promoter-reporter constructs and electrophoretic mobility shift assays, we found that the formation of a slowly migrating complex was required for full activation of the Stat3 gene. Thus, STAT3 activates the Stat3 gene in cooperation with an unidentified CRE-binding protein. This regulatory mechanism is similar to that of the junB gene, which is activated by IL-6 through the junB IL-6RE, which contains a low affinity STAT3-binding site and a CRE-like site.
Ichiba
M
M
Division of Molecular Oncology, Department of Oncology, Biomedical Research Center, Osaka University Medical School, 2-2 Yamadaoka, Suita City, Osaka 565, Japan.
Nakajima
K
K
Yamanaka
Y
Y
Kiuchi
N
N
Hirano
T
T
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D050796:STAT3 Transcription Factor; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494257:IRF1 protein, human; C494200:Il6st protein, mouse; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6; C494258:Irf1 protein, mouse; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130