Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB

• Published in: Genes & development Vol. 21; no. 11; pp. 1396 - 1408
• Main Authors: Yang, Jinbo, Liao, Xudong, Agarwal, Mukesh K, Barnes, Laura, Auron, Philip E, Stark, George R
• Format: Journal Article
• Language: English
• Published: United States 01.06.2007
• Subjects: Binding Sites; Biomarkers - metabolism; Breast - cytology; Breast - metabolism; Cell Nucleus - metabolism; Cells, Cultured - metabolism; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Chromatin Immunoprecipitation; Epithelial Cells - metabolism; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunoprecipitation; Interleukin-6 - pharmacology; NF-kappa B - genetics; NF-kappa B - metabolism; Nuclear Localization Signals; Oligonucleotide Array Sequence Analysis; Phosphorylation; Promoter Regions, Genetic; Regulatory Elements, Transcriptional; Signal Transduction; STAT3 Transcription Factor - metabolism; Transcription, Genetic
• ISSN: 0890-9369; 1549-5477

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.