The Carboxyl-terminal Region of STAT3 Controls Gene Induction by the Mouse Haptoglobin Promoter

Haptoglobin (HP) is one of the major acute phase plasma proteins in the mouse, and its synthesis is additively induced by interleukin (IL)-6 and glucocorticoids. STAT3 serves as the mediator of the IL-6 receptor signal and appears to contribute to the transcriptional induction of acute phase protein genes. The carboxyl-terminal region of STAT3, consisting of an acidic domain and containing a serine phosphorylation site, has been proposed to contribute to the induction process. To assess the role of STAT3 in the transcriptional control of the HP promoter, we applied two mutant forms of STAT3: one with a deletion of the carboxyl-terminal 55 amino acid residues, STAT3Δ55C, and the other with a substitution of serine 727 to alanine, STAT3SA. Like the wild-type STAT3, both mutant STAT3 forms are activated by the signal-transducing subunit of the IL-6 receptor, gp130, or by co-transfected IL-3 receptor. Ectopic expression and activation of wild-type STAT3 or STAT3SA in HepG2 hepatoma cells similarly enhance transcription through the IL-6-response element of the HP promoter. This enhancement is specific for STAT3 and cannot be reproduced by STAT1 or STAT5. In contrast, STAT3Δ55C inhibits IL-6-induced transcriptional activation. Interestingly, whereas receptor-activated STAT3 also enhances stimulation of the haptoglobin promoter by dexamethasone through the glucocorticoid receptor, activated STAT3Δ55C reduces the regulation below the level achieved by the glucocorticoid receptor alone. This transdominant action by STAT3Δ55C is dependent on a functional IL-6-responsive element. The data suggest that the carboxyl-terminal domain, but not its serine phosphorylation site of STAT3, is required for transcription as part of the hematopoietin receptor signaling as well as for cooperation with other transcription factors such as the glucocorticoid receptor. Haptoglobin (HP) is one of the major acute phase plasma proteins in the mouse, and its synthesis is additively induced by interleukin (IL)-6 and glucocorticoids. STAT3 serves as the mediator of the IL-6 receptor signal and appears to contribute to the transcriptional induction of acute phase protein genes. The carboxyl-terminal region of STAT3, consisting of an acidic domain and containing a serine phosphorylation site, has been proposed to contribute to the induction process. To assess the role of STAT3 in the transcriptional control of the HP promoter, we applied two mutant forms of STAT3: one with a deletion of the carboxyl-terminal 55 amino acid residues, STAT3Δ55C, and the other with a substitution of serine 727 to alanine, STAT3SA. Like the wild-type STAT3, both mutant STAT3 forms are activated by the signal-transducing subunit of the IL-6 receptor, gp130, or by co-transfected IL-3 receptor. Ectopic expression and activation of wild-type STAT3 or STAT3SA in HepG2 hepatoma cells similarly enhance transcription through the IL-6-response element of the HP promoter. This enhancement is specific for STAT3 and cannot be reproduced by STAT1 or STAT5. In contrast, STAT3Δ55C inhibits IL-6-induced transcriptional activation. Interestingly, whereas receptor-activated STAT3 also enhances stimulation of the haptoglobin promoter by dexamethasone through the glucocorticoid receptor, activated STAT3Δ55C reduces the regulation below the level achieved by the glucocorticoid receptor alone. This transdominant action by STAT3Δ55C is dependent on a functional IL-6-responsive element. The data suggest that the carboxyl-terminal domain, but not its serine phosphorylation site of STAT3, is required for transcription as part of the hematopoietin receptor signaling as well as for cooperation with other transcription factors such as the glucocorticoid receptor. Acute phase response is elicited by the various forms of inflammatory condition, tissue injury, and infection (1Kushner I. Mackiewicz A. Mackiewicz A. Kushner I. Baumann H. Acute Phase Proteins: Molecular Biology, Biochemistry, and Clinical Applications. CRC Press, Boca Raton, FL1993: 4-19Google Scholar). The recruitment of the systemic defense mechanisms is initiated by many cell types at the site of local inflammation and includes macrophages, mast cells, fibroblasts, and endothelial cells and involves the production, release, and distribution of several cytokines. A major component of the systemic acute phase response is the enhanced production of several plasma proteins in the liver that are collectively called acute phase plasma proteins (APPs) 1The abbreviations used are:APPacute phase plasma protein;HPhaptoglobin;ILinterleukin;IL-6RIL-6 receptor;IL-3RIL-3 receptor;bpbase pair;GRglucocorticoid receptor;C/EBPCAAT/enhancer-binding protein;GCSFgranulocyte colony-stimulating factor;GCSFRGCSF receptor;CATchloramphenicol acetyltransferase;EMSAelectrophoretic mobility shift assay;IL-6REinterleukin 6 response element;MAPKmitogen-activated protein kinase;PEA-3polyomavirus enhancer activator-3;SIEsis-inducible element;SIFsis-inducible factor. (1Kushner I. Mackiewicz A. Mackiewicz A. Kushner I. Baumann H. Acute Phase Proteins: Molecular Biology, Biochemistry, and Clinical Applications. CRC Press, Boca Raton, FL1993: 4-19Google Scholar). In most vertebrate species, haptoglobin (HP) is one of the core sets of APPs, and its synthesis is generally increased severalfold. In the mouse, the increase is 30-fold and exceptionally high (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar). HP functions as a hemoglobin-binding protein and is most effective in clearing free hemoglobin from the circulation (3Bowman B.H. Kurosky A. Adv. Hum. Genet. 1982; 12: 189-261Google Scholar). IL-6 is the major inducer of the hepatic production of most APPs, whereas IL-1 and tumor necrosis factor-α act only on a subset of APPs (4Baumann H. Gauldie J. Immunol. Today. 1994; 15: 74-80Google Scholar). Glucocorticoids or dexamethasone enhance the production of many APPs through yet-to-be defined mechanisms. The mouse HP gene is an example of APPs that are strongly induced by both IL-6 and dexamethasone (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar). acute phase plasma protein; haptoglobin; interleukin; IL-6 receptor; IL-3 receptor; base pair; glucocorticoid receptor; CAAT/enhancer-binding protein; granulocyte colony-stimulating factor; GCSF receptor; chloramphenicol acetyltransferase; electrophoretic mobility shift assay; interleukin 6 response element; mitogen-activated protein kinase; polyomavirus enhancer activator-3; sis-inducible element; sis-inducible factor. Signaling by the IL-6 receptor is mediated by the signal-transducing common subunit gp130 through Janus kinases associated with the cytoplasmic domain containing the Box-1 and Box-2 motifs (5Lütticken C. Wegenka U.M. Yuan J. Buschmann J. Schindler C. Ziemiecki A. Harpur A.G. Wilks A.F. Yasukawa K. Taga T. Kishimoto T. Barbieri G. Pellegrini S. Sendtner M. Heinrich P.C. Horn F. Science. 1994; 263: 89-92Google Scholar). Following phosphorylation on the tyrosine residue in the Box-3 motifs of gp130, STAT3 is recruited to the gp130 and is activated by receptor-associated Janus kinases (JAKs) through phosphorylation (6Stahl N. Farruggella T.J. Boulton T.G. Zhong Z. Darnell Jr., J.E. Yancopoulous G.D. Science. 1995; 267: 1349-1353Google Scholar). Activated STAT3 dimerizes, translocates to the nucleus, and binds to specific DNA sequences (7Zhong Z. Wen Z. Darnell Jr., J.E. Science. 1994; 264: 95-98Google Scholar). The interaction of STAT3 with specificcis-acting elements has been correlated with enhanced transcription of the responsive target genes including APPs (8Wegenka U.M. Buschmann J. Lutticken C. Heinrich P. Horn F. Mol. Cell. Biol. 1993; 13: 267-288Google Scholar, 9Lai C.-F. Ripperger J. Morella K.K. Wang Y. Gearing D.P. Fey G.H. Baumann H. J. Biol. Chem. 1995; 270: 14847-14850Google Scholar). Recent analyses have suggested that additional modifications of STAT3 protein alter its function as a transcriptional activator. Phosphorylation on serine 727 has been shown to enhance DNA binding affinity and activation of transcription (10Zhang X. Blenis J. Li H.-C. Schindler C. Chen-Kiang S. Science. 1995; 267: 1990-1994Google Scholar, 11Wen Z. Zhong Z. Darnell Jr., J.E. Cell. 1995; 82: 241-250Google Scholar). Deletion of the carboxyl-terminal region, as found in the STAT3β form, rendered the protein inactive as an activator of transcription and as a regulator of differentiation of the myeloid cell line M1 in response to IL-6 (12Shaefer T.S. Sanders L.K. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9097-9101Google Scholar, 13Caldenhoven E. van Dijk T.B. Solari R. Armstrong J. J. Biol. Chem. Scholar, M. M. S. K. M. Kishimoto T. S. Proc. Natl. Acad. Sci. U. S. A. Scholar). of STAT3 has for gene the action of STAT3 mutant in the of an gene promoter, has not been The promoter of the mouse HP gene has been as a to the of the carboxyl-terminal and the serine 727 phosphorylation site for regulation by and other hematopoietin in hepatic we have found that the HP promoter elements for induction by IL-6 and and includes two binding element at to and element at to the IL-6 response element element at to and the binding site to 6 S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar). glucocorticoid receptor binding site be in the mouse HP promoter, the dexamethasone response appears to be dependent on the of the and the response region at to of the HP promoter (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar). we the with STAT3 to transcription through the of the HP gene and the of the and STAT3 in induction by IL-6 and and HepG2 cells D.P. Science. in with and hepatoma cells, Biol. in with with containing IL-3 or GCSF dexamethasone the receptor H. Morella K.K. Wang Y. D. Gearing D.P. Mol. Cell. Biol. 1994; IL-3 receptor K. T. T. A. Proc. Natl. Acad. Sci. U. S. A. and T. N. A. Cell. glucocorticoid receptor R. S. S. K.R. Cell. and STAT3 C.-F. Ripperger J. Morella K.K. Wang Y. Gearing D.P. Fey G.H. Baumann H. J. Biol. Chem. 1995; 270: 14847-14850Google have been the promoter of the HP gene to to the transcription to the gene in (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar). In the the element to the of the region of HP promoter to 6 in the site of The serine 727 to in STAT3SA by with STAT3Δ55C by two amino acid residue of the by DNA and the forms the D. A. D. J. C. J.E. D. D. Cell. Scholar). cells by the H. 12: Scholar). a the cells in for with for cell K. Darnell Jr., J.E. Science. 1993; Scholar). HepG2 cells by the DNA Biol. 1994; 13: Scholar). This of cells in the as from in for the expression of the The a of and of as an K.R. Baumann H. Mol. Cell. Biol. Scholar). a cells with the for and of cell used to the of the of chloramphenicol to The to the expression of the co-transfected major protein K.R. Baumann H. Mol. Cell. Biol. and to the control as of at are reproduced in the of the cell containing of protein used for The high affinity sis-inducible element K. Darnell Jr., J.E. Science. 1993; as binding for STAT1 and STAT3, and as for K.K. C. S. N. Wang Y. J. Gearing D.P. D. Baumann H. J. Biol. Chem. 1995; 270: Scholar). the cell containing also on 6 or The proteins to and with STAT3 or cell with by enhanced cell from cells STAT3 or STAT3SA as for the of cell protein in a of of and with of and of activated for at by the by STAT3 from the with STAT3 and to for and To the role of STAT3 in the regulation of mouse HP gene we two mutant forms of STAT3: STAT3SA with a of the serine to at its carboxyl-terminal site, and STAT3Δ55C with a of the acidic carboxyl-terminal as in STAT3β (12Shaefer T.S. Sanders L.K. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9097-9101Google Scholar, 13Caldenhoven E. van Dijk T.B. Solari R. Armstrong J. J. Biol. Chem. but the additional by the the expression of the proteins by cells that in that that of the STAT3 The major of the proteins with the a of and STAT3SA with an forms STAT3 proteins forms in HepG2 cell of proteins on gene induction through the HP promoter. HepG2 cells with a of expression for the proteins and expression to a of In of used for of the protein in the of the of cells in The cells with IL-6 or GCSF for part of the cells in for of and the part used for cell containing and of protein used for and or with as binding protein in and proteins on the with the for gene HepG2 cells with a of as in consisting of the and expression for and proteins In of the cell and for with the or The of one is The stimulation in is the HepG2 cells with a of or and the of expression for STAT3, or STAT3Δ55C as The DNA in to a of with with IL-6 for and are to control IL-6 and STAT3 The activation of the proteins by gp130 by the co-transfected receptor, This receptor of the domain of the to the and the cytoplasmic domain of of The receptor is to a that also includes the cytoplasmic gp130 has been for the G. Yasukawa K. A. J. Biol. Chem. 1994; 269: Scholar, G. R. A. R. A. C. G. J. 1995; Scholar). of the receptor the that signaling function of gp130 be in cells and of the gp130 H. Morella K.K. Wang Y. D. Gearing D.P. Mol. Cell. Biol. 1994; Scholar, C.-F. Ripperger J. Morella K.K. Wang Y. Gearing D.P. Fey G.H. Baumann H. J. Biol. Chem. 1995; 270: Scholar). from cells with or GCSF that activated by the receptor and shown C.-F. Ripperger J. Morella K.K. Wang Y. Gearing D.P. Fey G.H. Baumann H. J. Biol. Chem. 1995; 270: 14847-14850Google in cells not with expression activated of proteins consisting of In the of STAT3, the binding for STAT3 K. Darnell Jr., J.E. Science. 1993; a of STAT3 and STAT1 as an additional below the STAT3 the with wild-type STAT3 and STAT3SA by the a and The not by but a mobility to the of the acidic that the for the on in STAT3Δ55C in cells, is in with data (12Shaefer T.S. Sanders L.K. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9097-9101Google Scholar, 13Caldenhoven E. van Dijk T.B. Solari R. Armstrong J. J. Biol. Chem. Scholar). The with STAT3 that the phosphorylation at tyrosine in STAT3 correlated with the DNA binding of the To in that STAT3Δ55C forms with STAT1 or STAT3 also 13Caldenhoven E. van Dijk T.B. Solari R. Armstrong J. J. Biol. Chem. we of expression for STAT3Δ55C, STAT3, and STAT1 DNA binding of the proteins activated through and by of STAT3Δ55C and STAT1 or STAT3 a shift STAT3Δ55C at high STAT3Δ55C expression level of that activated STAT3Δ55C to the nucleus, and from the wild-type STAT3 or STAT3SA not that to (10Zhang X. Blenis J. Li H.-C. Schindler C. Chen-Kiang S. Science. 1995; 267: 1990-1994Google at the level as wild-type STAT3 and to with we the the of STAT3 for cell containing STAT3 or STAT3SA in with and and that wild-type STAT3, but not not that the serine to a phosphorylation site in the of the two mutant STAT3 forms and also that proteins in activation by the gp130 and binding to DNA mutant forms the for in STAT3 function as an inducer of transcription through the HP promoter. To the role of proteins in the IL-6 regulation of the mouse HP promoter, we to the IL-6-responsive in hepatic cells, cells to a regulation of that not mouse hepatoma cells with HP gene expression have been we HepG2 cells as the for IL-6 (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar, 9Lai C.-F. Ripperger J. Morella K.K. Wang Y. Gearing D.P. Fey G.H. Baumann H. J. Biol. Chem. 1995; 270: 14847-14850Google Scholar, H. Morella K.K. Wang Y. D. Gearing D.P. Mol. Cell. Biol. 1994; Scholar). cells with or with expression for the various to the of proteins to signaling by and co-transfected we applied a that been for hepatoma cells DNA Biol. 1994; 13: we only a of HepG2 cells in the and protein expression in cells not the to the of the proteins by and activation of DNA binding through receptor by the and for STAT3 in cells with that in control or cells, and by the we that the of STAT3 proteins the level of STAT3 by at the level production of rendered of the receptor protein in the we by that the expression of cell The of that the expression of the increased by the action of and The response enhanced by with of or in the STAT3, as well as enhanced induction in GCSF and cells by In contrast, STAT3Δ55C induction by the not of the containing the domain of to by mechanisms the signaling by in HepG2 cells H. Morella K.K. Wang Y. D. Gearing D.P. Mol. Cell. Biol. 1994; analyses of IL-6 action only in cells co-transfected The of the STAT3 forms on gene regulation through the or not dependent on the of co-transfected STAT3 expression a enhancement of the signal by wild-type STAT3 and STAT3SA with expression of STAT3Δ55C expression the induction of the gene level in The element at to of the HP promoter is HP genes from and and has been as an IL-6-responsive element H. Morella K.K. S. Mol. Cell. Biol. Scholar). for a binding of the HP to STAT3 not be by the as used in we by functional cell that element the target of the regulation by of the core of the mouse HP in 6 a and HepG2 cells, with STAT3 forms The that the element responsive to IL-6 and that both STAT3 and STAT3SA similarly enhanced the for the HP promoter STAT3Δ55C The signaling functions of the STAT3 as shown in to be on by the signal-transducing including the proteins that are by or A of the signaling action of the STAT3 forms through activation by co-transfected a Box-3 in its cytoplasmic is in and STAT3, but is to STAT3 proteins Y. Morella K. Ripperger J. C.-F. Gearing D.P. Fey G.H. Baumann H. 1995; Scholar). shown in the not the HP promoter or in with wild-type STAT3 or a induction In the STAT3Δ55C The HP promoter also mediated a induction by dexamethasone in the of IL-6 the of dexamethasone and IL-6 The dexamethasone but not the IL-6 increased by co-transfected A enhanced dexamethasone action achieved with expression a in part to of E. M. F. F. Scholar). The of the a action in the induction through the HP promoter. wild-type STAT3, to enhance the IL-6 response and the dexamethasone the response to IL-6 and dexamethasone A and STAT3Δ55C on dexamethasone activated by IL-6 the dexamethasone response to In the of the induction of the HP promoter enhanced by dexamethasone by STAT3 wild-type or STAT3Δ55C In contrast, with the of IL-6 and STAT3Δ55C, but not STAT3 gene regulation below the level of that achieved by dexamethasone This of STAT3Δ55C specific to the HP promoter The not to dexamethasone in the of the that the through the proteins with the To that dexamethasone is of not only but also the mouse HP gene HP gene in HepG2 cells not to H. Morella K.K. S. Mol. Cell. Biol. we to the mouse hepatoma cell have shown that cells to dexamethasone by increased production of haptoglobin H. J. Biol. the cells to to cytokines. cells of as an for the response elements of the HP shown in a of cells to a increase of HP and action in cells with protein from that the induced HP gene The in HepG2 cells suggested that the promoter, but not its is the target of the To assess the specific of wild-type and mutant STAT3 to the action of on HP promoter, we the STAT3 of the regulation by the activation in induction of the gene with of STAT3 expression a of wild-type STAT3 and an of STAT3Δ55C expression we an of a of STAT3Δ55C in as well as IL-3 cells a of STAT3Δ55C, the transdominant action of the protein This of STAT3Δ55C on HP promoter in and cells in the of to that at and of and STAT3Δ55C the two proteins are and that the STAT3 high STAT3Δ55C and as a The data also suggest that a action and STAT3 is that in part the The carboxyl-terminal of STAT3 is in that and as in STAT3Δ55C an is of the mouse HP promoter (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google a role of and for expression The a role of STAT3 in IL-6 most through the and To the functional of the in the promoter we the core of at as in 6 A. and HepG2 cells 6 The two expression and stimulation by both IL-6 and dexamethasone been The of the two binding 6 S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google we by not suggest that the a role in expression and in the induction by dexamethasone and The of in the HP promoter on the specific function of STAT3 and in HepG2 cells transcription 6 STAT3 activated by but on the In contrast, a induction of the The action with wild-type HP promoter and also not by and wild-type STAT3 or STAT3Δ55C not The data the that STAT3 through interaction with a functional with and that the of STAT3 is for with transcriptional Acute phase regulation of hepatic HP gene expression is mediated by M. Baumann H. G. M. M. Kishimoto T. R. H. G. 1994; Scholar). additional factors to be such as factors and including to the acute phase induction (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar, H. Gauldie J. Immunol. Today. 1994; 15: 74-80Google Scholar, H. J. Biol. Scholar). signaling with factors have been proposed for T. S. M. Taga T. 1995; of act on the HP gene (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar, H. Morella K.K. Z. J. Biol. Chem. 267: Scholar, S. H. T. S. Y. T. T. Kishimoto T. J. Scholar). The of an role of STAT3 in hematopoietin receptor in that of gp130 as part of the to the mouse HP gene promoter in hepatic the by two mutant STAT3 proteins that been to act as specific and applied to the signal mechanisms. The STAT3SA by the serine phosphorylation site at residue as a DNA binding (10Zhang X. Blenis J. Li H.-C. Schindler C. Chen-Kiang S. Science. 1995; 267: 1990-1994Google and as a Z. Zhong Z. Darnell Jr., J.E. Cell. 1995; 82: 241-250Google Scholar). data that STAT3SA used as signaling by gp130 or in hepatic cells wild-type the and as that the hematopoietin receptor STAT3 as a signal in hepatic cells, gene induction the of the of serine we that activation of or protein that act serine 727 Z. Zhong Z. Darnell Jr., J.E. Cell. 1995; 82: 241-250Google Scholar, A. E. J.E. J. Biol. Chem. not a role in HP gene This is in part by that of hepatic cells with that the or protein of the hematopoietin receptor by or enhance the action of IL-6 on genes or H. H. J. Biol. Chem. 263: Scholar, Wang Y. Baumann H. J. Biol. Chem. Scholar). In that E. and serine phosphorylation of STAT3 J.E. J. Biol. Chem. reduces the IL-6 induction of genes H. H. J. Biol. Chem. 263: Scholar, Wang Y. Baumann H. J. Biol. Chem. Scholar). that phosphorylation at serine 727 not be an for signaling but we cannot that phosphorylation at other or of STAT3 (10Zhang X. Blenis J. Li H.-C. Schindler C. Chen-Kiang S. Science. 1995; 267: 1990-1994Google J.E. J. Biol. Chem. Scholar). The mutant STAT3, STAT3Δ55C, has been on the of (10Zhang X. Blenis J. Li H.-C. Schindler C. Chen-Kiang S. Science. 1995; 267: 1990-1994Google or J. S. K. F. Fey G.H. J. Biol. Chem. 1995; 270: to be inactive as an inducer of transcription and to act as a transdominant or of wild-type The of action from the action of the tyrosine mutant STAT3 by of to as a of the signaling at the receptor level A. M. J. Biol. Chem. Scholar). STAT3Δ55C has an wild-type function in to recruitment to the receptor, activation by receptor-associated and DNA STAT3Δ55C signaling by to transcription in This that the carboxyl-terminal acidic have to the acidic of other transcription factors such as or with transcription factors and G. R. Cell. Scholar). STAT3Δ55C STAT3β (12Shaefer T.S. Sanders L.K. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9097-9101Google but by not an acid In with the E. van Dijk T.B. Solari R. Armstrong J. J. Biol. Chem. STAT3Δ55C is STAT3β in two STAT3Δ55C not DNA binding in cells not with IL-6 or and STAT3Δ55C DNA binding but to The that STAT3 forms of The of STAT3Δ55C on the co-transfected HP gene A action is also to on IL-6-responsive genes that are also to to the of the such an not be in the HepG2 by to HepG2 cells and H. many a STAT3Δ55C expression level that to the action of the in the IL-6 induction of HP by to the data a action of STAT3Δ55C in the of an gene promoter we an role for STAT3Δ55C in the of transcription through the HP promoter This function of STAT3Δ55C to be activated by IL-6 that STAT3Δ55C with the of the HP promoter and action of the the carboxyl-terminal of STAT3, by its appears to the have not been to a binding of the glucocorticoid receptor with the HP promoter or an interaction of the glucocorticoid receptor with the that the glucocorticoid receptor at a site from the DNA E. M. F. F. Scholar). The with cells at an that on protein the for regulation through the HP promoter is shown in 6 the promoter defined interaction response elements that two A and for that the response element or and a site that is to the mouse HP gene (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google Scholar). A site for the interaction of the the (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google has not been is to STAT3 but appears also to be a target of a for expression and the dexamethasone response 6 IL-6 has two is the activation of STAT3 that with the or associated proteins or the factors S. R. J. Scholar). The other is the production and of H. Morella K.K. Z. J. Biol. Chem. 267: Scholar, S. H. T. S. Y. T. T. Kishimoto T. J. Scholar, D.P. A. F. R. G. 1993; Scholar). binds to the HP promoter, HP transcription (2Pajovic S. Jones V.E. Prowse K.R. Berger F.G. Baumann H. J. Biol. Chem. 1994; 269: 2215-2224Google and appears to enhance the of STAT3 and STAT3 is to transcription through the to an of induction that is to that of STAT3 through the HP promoter, an of the is we that the of STAT3 and as for the HP promoter, be as effective as a of several as for the The is or with the promoter in with the associated with STAT3, as a of IL-6 with a transcription is achieved through the that is at site in cells not with IL-6 STAT3Δ55C is as effective in binding to DNA as STAT3, similarly with and the factors but is to with the the J. Ripperger and G. Fey for STAT3 K. and Wang for C. for of the and and for