AUTOREGULATION OF THE STAT3 GENE THROUGH COOPERATION WITH A CAMP-RESPONSIVE ELEMENT-BINDING PROTEIN

STAT3 (signal transducer and activator of transcription (3) under bar) is a key transcription factor mediating the signals for a variety of cytokines, including interleukin-6 (IL-6), The Stat3 gene itself is ac tivated by IL-6 signals, We show that the region of the signal-transdu cing subunit, gp130, essential for STAT3 activation, is also required for activation of the Stat3 gene. To elucidate the mechanisms activati ng the Stat3 gene, we identified an IL-6 response element (IL-6RE) in the Stat3 gene promoter containing both a low affinity STAT3-binding e lement and a cAMP-responsive element (CRE), Electrophoretic mobility s hift assays showed that IL-6 induced a slowly migrating complex on the IL-6RE containing a STAT3 homodimer and an unidentified CRE-binding p rotein, With the combination of transient transfection assays using mu tant Stat3 promoter-reporter constructs and electrophoretic mobility s hift assays, we found that the formation of a slowly migrating complex was required for full activation of the Stat3 gene. Thus, STAT3 activ ates the Stat3 gene in cooperation with an unidentified CRE-binding pr otein, 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 l ow affinity STAT3-binding site and a CRE-like site.