title: Impact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity.
abstract: The transcription factor STAT3 is constitutively active in many cancers, where it mediates important biological effects, including cell proliferation, differentiation, survival, and angiogenesis. The N-terminal domain (NTD) of STAT3 performs multiple functions, such as cooperative DNA binding, nuclear translocation, and protein-protein interactions. 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 STAT3 or STAT3 from which NTD was deleted. NTD deletion reduced the cytokine-induced expression of specific STAT3 target genes by decreasing STAT3 binding to their regulatory regions. To better understand the potential mechanisms of this effect, we determined the crystal structure of the STAT3 NTD and identified a dimer interface responsible for cooperative DNA binding in vitro. We also observed an Ni(2+)-mediated oligomer with an as yet unknown biological function. Mutations on both dimer and Ni(2+)-mediated interfaces affected the cytokine induction of STAT3 target genes. These studies shed light on the role of the NTD in transcriptional regulation by STAT3 and provide a structural template with which to design STAT3 NTD inhibitors with potential therapeutic value.
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA Postdoctoral Program, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: Tiancen
authors.initials: T
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Yeh
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jaison
authors.initials: J
authors.lastname: Jacob
authors.affiliation: Biophysical Collaborative Access Team/Illinois Institute of Technology, Sector 18ID (Advanced Photon Source, Argonne National Laboratory), Lemont, Illinois, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chakravarthy
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA rajiv.chopra@novartis.com david_frank@dfci.harvard.edu.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA Biophysical Collaborative Access Team/Illinois Institute of Technology, Sector 18ID (Advanced Photon Source, Argonne National Laboratory), Lemont, Illinois, USA Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA rajiv.chopra@novartis.com david_frank@dfci.harvard.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D053605:Leukemia Inhibitory Factor / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000737:chemistry* / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse