title: Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB.
abstract: gp130-linked cytokines such as interleukin-6 (IL-6) stimulate the formation of tyrosine-phosphorylated signal transducer and activator of transcription 3 (P-STAT3), which activates many genes, including the STAT3 gene itself. The resulting increase in the concentration of unphosphorylated STAT3 (U-STAT3) drives a second wave of expression of genes such as RANTES, IL6, IL8, MET, and MRAS that do not respond directly to P-STAT3. Thus, U-STAT3 sustains cytokine-dependent signaling at late times through a mechanism completely distinct from that used by P-STAT3. Many U-STAT3-responsive genes have kappaB elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NFkappaB (U-NFkappaB), in competition with IkappaB. The U-STAT3/U-NFkappaB complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of kappaB-dependent genes. Additional genes respond to U-STAT3 through an NFkappaB-independent mechanism. The role of signal-dependent increases in U-STAT3 expression in regulating gene expression is likely to be important in physiological responses to gp130-linked cytokines and growth factors that activate STAT3, and in cancers that have constitutively active P-STAT3.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
authors.forename: Xudong
authors.initials: X
authors.lastname: Liao
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Agarwal
authors.forename: Laura
authors.initials: L
authors.lastname: Barnes
authors.forename: Philip E
authors.initials: PE
authors.lastname: Auron
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
mesh_terms: D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D001940:Breast / Q000166:cytology / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D018946:Chemokine CCL5; D015850:Interleukin-6; D016328:NF-kappa B; D019913:Nuclear Localization Signals; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human