Hu, Tiancen, Yeh, Jennifer, Pinello, Luca, Jacob, Jaison, Yuan, Guo-Cheng, Harrison, Stephen, Frank, David and Chopra, Rajiv (2015) The N-terminal domain of STAT3 plays a critical role in STAT3-dependent transcriptional activity. Molecular and Cellular Biology, 35 (19). pp. 3284-3300. ISSN 1098-5549

Abstract

The transcription factor STAT3 is constitutively active in and drives the proliferation of many cancers. Its ~15 kD N-terminal domain (NTD) mediates various functions such as cooperative DNA binding and nuclear translocation. However, it is unclear which subsets of STAT3 target 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 or NTD-deleted STAT3. NTD deletion reduced cytokine-induced expression of certain STAT3target genes by decreasing STAT3 DNA binding to these gene regulatory regions. These reductions can be attributed to loss of NTD-mediated cooperativity and perhaps also to loss of binding to other transcription factors. Next we determined the crystal structure of the STAT3 NTD and identified a dimer interface functional in cooperative DNA binding in vitro. We also observed a Ni2+-mediated tetramer interface in the crystal linking four STAT3 dimers into an octamer which might imply interesting biology. Mutations on both dimer and tetramer interfaces reduced cytokine induction of STAT3 target genes. These studies shed light on a novel aspect of STAT3 transcriptional activity and also provide structural information to design STAT3 NTD inhibitors with potential therapeutic value.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/24181