Ser727‐dependent transcriptional activation by association of p300 with STAT3 upon IL‐6 stimulation

Activation of the signal transducer and activator of transcription 3 (STAT3) in response to interleukin‐6 (IL‐6) type cytokines involves both phosphorylation of Tyr705, which enables dimerization, nuclear translocation and DNA binding, as well as ser727 phosphorylation. Here, we describe that the 65 C‐terminal amino acids of STAT3 can function as an independent transcription activation domain (TAD), particularly when a negative charge is introduced at position 727 by mutation of the serine residue into aspartate. The strong transcriptional activity of the C‐terminal STAT3 Ser727Asp TAD is coupled to a constitutive association with the co‐activator p300. In HepG2 cells, p300 associates with STAT3 upon IL‐6 stimulation, and overexpression of p300 enhances the transcriptional activity of STAT3α, but not of STAT3β or STAT3 Ser727Ala. We conclude that Ser727 phosphorylation in the C‐terminal region of STAT3 is required for transactivation by association with p300.