Impact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity

• DOI: 10.1128/mcb.00060-15
• Publication Date: 2015-07-14T02:20:17Z
• Authors: Tiancen Hu; Jennifer E. Yeh; Luca Pinello; Jaison Jacob; Srinivas Chakrava...; Guo-Cheng Yuan; Rajiv Chopra; David A. Frank
• Keywords: Models, Molecular; STAT3 Transcription Factor; Transcriptional Activation; 0301 basic medicine; Base Sequence; Transcription, Genetic; Molecular Sequence Data; Crystallography, X-Ray; Leukemia Inhibitory Factor; Protein Structure, Secondary; Protein Structure, Tertiary; Up-Regulation; Mice; 03 medical and health sciences; Animals; Amino Acid Sequence; Protein Multimerization; Cells, Cultured; Protein Binding

The transcription factor STAT3 is constitutively active in many cancers, where it mediates important biological effects, including cell proliferation, differentiation, survival, and angiogenesis. N-terminal domain (NTD) of performs multiple functions, such as cooperative DNA binding, nuclear translocation, protein-protein interactions. However, unclear which subsets target genes depend on the NTD for transcriptional regulation. To identify genes, we compared gene expression STAT3-null mouse embryonic fibroblasts (MEFs) stably expressing wild-type or from was deleted. deletion reduced cytokine-induced specific by decreasing binding to their regulatory regions. better understand potential mechanisms this effect, determined crystal structure identified a dimer interface responsible vitro. We also observed an Ni2+-mediated oligomer with yet unknown function. Mutations both interfaces affected cytokine induction genes. These studies shed light role regulation provide structural template design inhibitors therapeutic value.