Impact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity
2015
The transcription factor
STAT3is constitutively active in many cancers, where it mediates important biological effects, including cell proliferation, differentiation, survival, and angiogenesis. The N-terminal domain (NTD) of
STAT3performs
multiple functions, such as cooperative DNA binding, nuclear translocation, and protein-protein interactions. However, it is unclear which subsets of
STAT3target genes depend on the NTD for
transcriptional regulation. To identify such genes, we compared gene expression in
STAT3-null
mouse embryonic fibroblasts(MEFs) stably expressing wild-type
STAT3or
STAT3from which NTD was deleted. NTD deletion reduced the cytokine-induced expression of specific
STAT3target genes by decreasing
STAT3binding to their regulatory regions. To better understand the potential mechanisms of this effect, we determined the crystal structure of the
STAT3NTD and identified a dimer interface responsible for cooperative DNA binding in vitro. We also observed an Ni2+-mediated oligomer with an as yet unknown biological function. Mutations on both dimer and Ni2+-mediated interfaces affected the cytokine induction of
STAT3target genes. These studies shed light on the role of the NTD in
transcriptional regulationby
STAT3and provide a structural template with which to design
STAT3NTD inhibitors with potential therapeutic value.
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