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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.
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PMID:A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. 750 5

Interleukin-6 (IL-6) and gamma interferon (IFN-gamma) induce a partially overlapping set of genes, including the genes for interferon regulatory factor 1 (IRF-1), intercellular adhesion molecule 1 (ICAM-1), and the acute-phase protein alpha 2-macroglobulin. We report here that the rat alpha 2-macroglobulin promoter is activated by IFN-gamma in human hepatoma (HepG2) cells and that the IFN-gamma response element maps to the same site previously defined as the acute-phase response element (APRE), which binds the IL-6-activated transcription factor APRF (acute-phase response factor). As was reported for fibroblasts, the IFN-gamma-regulated transcription factor GAF is phosphorylated at tyrosine after IFN-gamma treatment of HepG2 cells. IFN-gamma posttranslationally activates a protein which specifically binds to the alpha 2-macroglobulin APRE. This protein is shown to be identical or closely related to GAF. Although APRF and GAF are shown to represent different proteins, their binding sequence specificities are very similar. APRF and GAF bind equally well to the APRE sequences of various acute-phase protein genes as well as to the IFN-gamma response elements of the IRF-1, ICAM-1, and other IFN-gamma-inducible genes. Transient transfection analysis revealed that the IFN-gamma response elements of the IRF-1 and ICAM-1 promoters are able to confer responsiveness to both IFN-gamma and IL-6 onto a heterologous promoter. Therefore, APRF and GAF are likely to be involved in the transcriptional induction of these immediate-early genes by IL-6 and IFN-gamma, respectively. Taken together, these results demonstrate that two functionally distinct hormones, IL-6 and IFN-gamma, act through common regulatory elements to which different transcription factors sharing almost the same sequence specificity bind.
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PMID:The signalling pathways of interleukin-6 and gamma interferon converge by the activation of different transcription factors which bind to common responsive DNA elements. 750 45

Acute-phase response factor (APRF) is a transcription factor that binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes. We report here the purification and cloning of APRF. APRF exhibits a 52.5% overall homology at the amino acid level with p91, a component of the interferon (IFN)-stimulated gene factor 3 complexes. The cloned APRF protein is tyrosine phosphorylated and translocated into the nucleus in response to IL-6, but not in response to IFN-gamma. Tyrosine phosphorylation was also observed in response to other cytokines, such as leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor, whose receptors share the IL-6 receptor signal transducer gp130. In contrast, we observed that p91 is not tyrosine phosphorylated in response to IL-6. These results suggest that this novel p91-related protein may play a major role in the gp130-mediated signaling pathway and that selective activation of p91-related factors may explain the diversity of cellular responses to different cytokines.
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PMID:Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. 751 51

We have studied transcription factors that are coupled to the activation of cytokine receptors in liver and in mammary epithelial cells. Interleukin-6 (IL-6) causes the rapid activation of the acute-phase response factor (APRF) in the liver of animals during acute inflammation and in cultured human hepatoma cells (HepG2) and induces the transcription of the acute-phase protein genes, e.g. alpha 2-macroglobulin (alpha 2-M). In the mammary gland and in cultured HC11 mammary epithelial cells, milk protein genes, e.g. beta-casein, are induced by the lactogenic hormones, insulin, glucocorticoids, and PRL. The induction of the beta-casein gene promoter is preceded by the activation of the mammary gland factor (MGF). We have compared the DNA binding sequences of APRF and MGF, 5'-CTTCTT/GGGAATT-3', and have found that they coincide in 11 of 12 positions. Bandshift experiments and oligonucleotide competition experiments showed that both factors, MGF and APRF, are able to bind to the IL-6 response element of the alpha 2-M gene promoter and to the lactogenic hormone response element of the beta-casein gene promoter with very similar specificities. Partial proteolytic digestion of APRF and MGF DNA complexes yielded similar clipping patterns. The UV cross-linked DNA complexes of both transcription factors were of the same apparent molecular mass. IL-6 activation of APRF in HepG2 cells can be observed within minutes. MGF induction by PRL in HC11 cells occurs with similar kinetics. The synergistic action of glucocorticoids and PRL is necessary for the induction of the beta-casein gene, but PRL is sufficient for MGF activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mammary gland factor activated by prolactin on mammary epithelial cells and acute-phase response factor activated by interleukin-6 in liver cells share DNA binding and transactivation potential. 751 23

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G-CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.
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PMID:Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. 752 88

Cytokines and growth factors elicit responses in target cells through induction of gene expression. Signaling mechanisms leading to gene transcription from cell surface receptors often require tyrosine phosphorylation. A family of transcription factors comprising the interferon (IFN)-stimulated gene factor 3 (ISGF3) multimeric complex are phosphorylated and activated in response to interferon. We describe a protein 50% identical to the 91-kDa subunit of ISGF3 that constitutes the acute phase response factor (APRF). This protein was rapidly activated by interleukin-6 to bind an enhancer element common to genes activated in liver cells during the acute phase response to inflammation. Remarkably, APRF was also activated by IFN alpha, IFN gamma, epidermal growth factor, platelet-derived growth factor, colony stimulating factor-1, and the cytokines leukemia inhibitory factor and oncostatin M. The growth factors also activated a third, distinct but related, DNA-binding protein in addition to APRF and p91. This novel factor or a closely related one, but neither APRF nor p91, was also activated in lymphoid cells by interleukin-2, erythropoietin, and interleukin-3. Activation of APRF, p91, and additional members of the ISGF3 family is thus a general feature of a wide variety of signaling pathways, integrating diverse signals through common transcriptional regulators.
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PMID:Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. 752 73

Interferons (IFNs), as well as some interleukins, growth factors, and hormones, all induce tyrosine phosphorylation of STAT1 and additional transcription factors of similar sizes. These factors are activated to translocate to nucleus and bind to enhancers of consensus sequence TTnCnnnAA (gamma-IFN activated sequence-like enhancers). In mammary cells or hybridoma B9 cells, four distinct tyrosine-phosphorylated transcription complexes activated by interleukin-6 (IL-6) and IFN-beta were observed: pIRFA and complexes I, II, and III (of increasing electrophoretic mobility). The factors have unequal affinities for enhancers of different genes; they are activated with distinct kinetics and to different extents by IL-6 and IFNs. The pIRFA band isolated from IL-6-stimulated B9 hybridoma cells revealed three DNA-interacting components: two large subunits of 91 and 98 kDa, as well as a small component of 46 kDa not seen in other complexes analyzed. One of the large pIRFA subunits may be APRF/STAT3, since pIRFA reacted with anti-APRF antibodies as do complexes I and II. However, pIRFA did not react with antibodies to STAT1, indicating STAT1 is not the other large component of pIRFA. Complex II, which reacted to anti-acute phase response factor antibodies also reacted to anti-STAT1 antibodies, whereas complex III reacted only to anti-STAT1 and was the only complex resistant to N-ethylmaleimide. By its multimeric subunit structure and its cytokine and enhancer sequence specificities, the slowly migrating pIRFA band appears as a novel tyrosine-phosphorylated transcription complex acting on a subset of gamma-IFN activated sequence-like enhancers.
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PMID:Interleukin-6 signaling via four transcription factors binding palindromic enhancers of different genes. 752 3

The cytokine interleukin-6 (IL-6) rapidly activates a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation. Activation and DNA binding of APRF are inhibited by inhibitors of protein tyrosine kinases but not serine/threonine kinases. However, immediate-early gene induction by IL-6 and, as we show here, stimulation of the promoters of the genes for alpha 2-macroglobulin, Jun-B, and intercellular adhesion molecule-1 (ICAM-1) are blocked by the serine/threonine kinase inhibitor H7. We now show that IL-6 triggers a delayed phosphorylation of APRF at serine resudues which can be reversed in vitro by protein phosphatase 2A and is also inhibited by H7. Therefore, APRF serine phosphorylation is likely to represent a crucial event in IL-6 signal transduction leading to target gene induction.
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PMID:Interleukin-6-induced serine phosphorylation of transcription factor APRF: evidence for a role in interleukin-6 target gene induction. 753 7

Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the alpha 2-macroglobulin, fibrinogen, and alpha 1-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-kappa B, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.
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PMID:Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. 767 52

The mechanism by which the binding of growth hormone (GH) to its cell surface receptor elicits changes in gene transcription are largely unknown. The transcription factor Stat1/p91 has been shown to be activated by GH. Here we show that acute phase response factor or Stat3 f1p4an antigenically related protein), is also activated by GH. Stat3 has been implicated in the interleukin-6-dependent induction of acute phase response genes. GH promotes in 3T3-F442A fibroblasts the tyrosyl phosphorylation of a protein immunoprecipitated by antibodies to Stat3. This protein co-migrates with a tyrosyl phosphorylated protein from cells treated with leukemia inhibitory factor, a cytokine known to activate Stat3. Tyrosyl phosphorylated Stat3 is also observed in response to interferon-gamma. Stat3 is present in GH-inducible DNA-binding complexes that bind the sis-inducible element in the c-fos promoter and the acute phase response element in the alpha 2-macroglobulin promoter. The ability of GH to activate both Stat1 and Stat3 (i.e. increase their tyrosyl phosphorylation and ability to bind to DNA) suggests that gene regulation by GH involves multiple Stat proteins. Shared transcription factors among hormones and cytokines that activate JAK kinases provide an explanation for shared responses, while the ability of the different ligands to differentially recruit various Stat family members suggests mechanisms by which specificity in gene regulation could be achieved.
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PMID:Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. 787 44


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