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

¹ Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA; ² Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA

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 B elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NFB (U-NFB), in competition with IB. The U-STAT3/U-NFB complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of B-dependent genes. Additional genes respond to U-STAT3 through an NFB-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.

[Keywords: Gene chip; gene transcription; IL-6; Jak–Stat; NFB]

Received March 20, 2007; revised version accepted April 9, 2007.

E-MAIL starkg{at}ccf.org; FAX (216) 444-0512.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1553707

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