Inhibitory Cross-talk between STAT5b and Liver Nuclear Factor HNF3β

STAT5b is repeatedly activated in rodent liver by the male pattern of intermittent plasma growth hormone (GH) stimulation and is required to maintain the GH pulse-regulated, male-specific pattern of liver gene expression. We presently investigate the interactions between STAT5b and hepatocyte-enriched nuclear factors (HNFs) that contribute to regulation of GH pulse-inducible, male-specific liver cytochrome P-450 (CYP) genes. STAT5 binding sites were identified in the 5′-flank of the adult male-expressed genesCYP2A2 (nucleotides −2255 to −2247), CYP4A2(nucleotides −1872 to −1864), and CYP2C11 (nucleotides −1150 to −1142). STAT5-DNA complexes were formed by eachCYP sequence with nuclear extract from GH pulse-activated male, but not female, rat liver. TheCYP2C11 STAT5 site, which is flanked by HNF3 consensus sequences, conferred STAT5b-inducible reporter gene activity in GH-treated HepG2 cells. trans-Activation of the intactCYP2C11 promoter (1.8-kilobase 5′-flank) was strongly induced by the liver nuclear factors HNF1α and HNF3β but, unexpectedly, was inhibited by GH-activated STAT5b. This STAT5b inhibitory effect could be reversed by HNF1α and reflects a functional antagonism between STAT5b and HNF3β, as evidenced by the inhibition of HNF3β DNA binding and transcriptional activity by STAT5b. HNF3β, in turn, inhibited STAT5b by a novel mechanism that leads to suppression of GH-inducible STAT5b tyrosine phosphorylation, DNA binding activity, and transcriptional activity. The potential for GH-activated STAT5b to stimulate male-specific liver CYPexpression can thus be modulated by HNF3β, highlighting the complex interrelationship between STAT5b and liver transcription factors controlling expression of GH-regulated CYPgenes. STAT5b is repeatedly activated in rodent liver by the male pattern of intermittent plasma growth hormone (GH) stimulation and is required to maintain the GH pulse-regulated, male-specific pattern of liver gene expression. We presently investigate the interactions between STAT5b and hepatocyte-enriched nuclear factors (HNFs) that contribute to regulation of GH pulse-inducible, male-specific liver cytochrome P-450 (CYP) genes. STAT5 binding sites were identified in the 5′-flank of the adult male-expressed genesCYP2A2 (nucleotides −2255 to −2247), CYP4A2(nucleotides −1872 to −1864), and CYP2C11 (nucleotides −1150 to −1142). STAT5-DNA complexes were formed by eachCYP sequence with nuclear extract from GH pulse-activated male, but not female, rat liver. TheCYP2C11 STAT5 site, which is flanked by HNF3 consensus sequences, conferred STAT5b-inducible reporter gene activity in GH-treated HepG2 cells. trans-Activation of the intactCYP2C11 promoter (1.8-kilobase 5′-flank) was strongly induced by the liver nuclear factors HNF1α and HNF3β but, unexpectedly, was inhibited by GH-activated STAT5b. This STAT5b inhibitory effect could be reversed by HNF1α and reflects a functional antagonism between STAT5b and HNF3β, as evidenced by the inhibition of HNF3β DNA binding and transcriptional activity by STAT5b. HNF3β, in turn, inhibited STAT5b by a novel mechanism that leads to suppression of GH-inducible STAT5b tyrosine phosphorylation, DNA binding activity, and transcriptional activity. The potential for GH-activated STAT5b to stimulate male-specific liver CYPexpression can thus be modulated by HNF3β, highlighting the complex interrelationship between STAT5b and liver transcription factors controlling expression of GH-regulated CYPgenes. growth hormone cytochrome P-450 signal transducer and activator of transcription luciferase nucleotide hepatocyte nuclear factor electrophoretic mobility shift assay CCAAT/enhancer-binding protein Growth hormone (GH)1 is secreted by the pituitary gland in a sex-dependent manner in both rodents (1Jansson J.-O. Ekberg S. Isaksson O. Endocr. Rev. 1985; 6: 128-150Crossref PubMed Scopus (661) Google Scholar) and humans (2Veldhuis J.D. Eur. J. Endocrinol. 1996; 134: 287-295Crossref PubMed Scopus (87) Google Scholar). In male rats, GH is released into circulation every ∼3–3.5 h, giving a repeated, pulsatile plasma hormone pattern (3Tannenbaum G.S. Martin J.B. Endocrinology. 1976; 98: 562-570Crossref PubMed Scopus (652) Google Scholar), which contrasts to the more frequent, nearly continuous profile of pituitary GH secretion seen in adult females. These sexually dimorphic plasma GH patterns directly regulate the sexually dimorphic pattern of liver gene expression, in particular, liver cytochrome P-450 (CYP) gene expression (4Shapiro B.H. Agrawal A.K. Pampori N.A. Int. J. Biochem. Cell Biol. 1995; 27: 9-20Crossref PubMed Scopus (225) Google Scholar, 5Waxman D.J. Chang T.K.H. Ortiz de Montellano P.R. Cytochrome P-450: Structure, Mechanism, and Biochemistry. 2nd Ed. Plenum Press, New York1995: 391-417Google Scholar). Well studied examples of sex-specific, GH-regulated liver CYPs include the male-specific androgen 16α- and 2α-hydroxylase CYP2C11, which is strongly induced at puberty in male but not female rat liver, and the steroid sulfate 15β-hydroxylase CYP2C12, which is exclusively expressed in adult female rat liver (6Waxman D.J. J. Steroid Biochem. Mol. Biol. 1992; 43: 1055-1072Crossref PubMed Scopus (89) Google Scholar, 7Mode A. J. Reprod. Fertil. Suppl. 1993; 46: 77-86PubMed Google Scholar). The sexual dimorphism of liver with respect to expression of these and other sex-dependent liver CYPs, including CYP2A2 and CYP4A2 (both male-specific in their expression), is regulated by GH at the level of transcription initiation (8Sundseth S.S. Alberta J.A. Waxman D.J. J. Biol. Chem. 1992; 267: 3907-3914Abstract Full Text PDF PubMed Google Scholar, 9Legraverend C. Mode A. Westin S. Strom A. Eguchi H. Zaphiropoulos P.G. Gustafsson J.-A. Mol. Endocrinol. 1992; 6: 259-266Crossref PubMed Scopus (117) Google Scholar). GH signaling is initiated by GH receptor dimerization at the cell surface, leading to activation of the GH receptor-associated tyrosine kinase JAK2. JAK2, in turn, activates multiple intracellular signaling proteins (10Herrington J. Smit L.S. Schwartz J. Carter-Su C. Oncogene. 2000; 19: 2585-2597Crossref PubMed Scopus (227) Google Scholar, 11Moutoussamy S. Kelly P.A. Finidori J. Eur. J. Biochem. 1998; 255: 1-11Crossref PubMed Scopus (104) Google Scholar, 12Waxman D.J. Frank S.J. Conn P.M. Means A. Principles of Molecular Regulation. Humana Press, Totowa, NJ2000: 55-83Google Scholar). One such protein, the transcription factor STAT5b, displays a unique GH pulse responsiveness in rat liver (13Waxman D.J. Ram P.A. Park S.H. Choi H.K. J. Biol. Chem. 1995; 270: 13262-13270Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). The intermittent stimulation of liver cells by successive plasma GH pulses triggers a rapid and repeated tyrosine phosphorylation and nuclear translocation of STAT5b in adult male rats. By contrast, in adult female rats, the more continuous pattern of GH exposure down-regulates GH receptor-JAK2 activity, leading to a low steady-state level of the transcriptionally active, nuclear STAT5b (14Choi H.K. Waxman D.J. Endocrinology. 1999; 140: 5126-5135Crossref PubMed Scopus (75) Google Scholar, 15Choi H.K. Waxman D.J. Endocrinology. 2000; 141: 3245-3255Crossref PubMed Scopus (98) Google Scholar, 16Tannenbaum G.S. Choi H.K. Gurd W. Waxman D.J. Endocrinology. 2001; 142: 4599-4606Crossref PubMed Scopus (59) Google Scholar). A close correlation between STAT5b nuclear translocation and sex-specific liver gene expression is also seen in mouse liver (17Sueyoshi T. Yokomori N. Korach K.S. Negishi M. Mol. Pharmacol. 1999; 56: 473-477Crossref PubMed Scopus (60) Google Scholar). Targeted gene disruption studies establish that STAT5b, but not the closely related (>90% identical) STAT5a, plays a critical in the sex-dependent of the liver to GH Waxman D.J. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). male a of sexually dimorphic liver gene expression in to a of pulsatile growth Park S.H. Ram P.A. Waxman D.J. S. A. PubMed Scopus Google Scholar, S.H. Waxman D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. M. S. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). By contrast, is a and of and signaling by in the gland W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the studies for STAT5b in the male-specific pattern of liver gene expression, the of the gene STAT5b to the sexual dimorphism of the liver In the of the GH-activated STAT5b is to with the of promoter activity by transcription and HNF3β N. Park S.H. Waxman D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). to the sexual dimorphic expression of also D.J. S. Choi H.K. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, O. H. Gustafsson J. Mode A. S. A. PubMed Scopus Google Scholar, C. N. Mode A. Gustafsson J.A. M. Mol. Endocrinol. 1998; Google Scholar, T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In the of the promoter the of A. H. Mode A. C. J.A. DNA Cell Biol. PubMed Scopus Google Scholar), but the of other functional and the potential of STAT5b and liver transcription factors in transcription of gene not liver transcription factors contribute to the expression of These include the protein CCAAT/enhancer-binding proteins the factor the nuclear receptor and the J. 1996; PubMed Scopus Google Scholar). These liver transcription factors in unique to a complex of expression is by and inhibited by M. Mol. Endocrinol. 2000; PubMed Scopus Google Scholar), HNF3β the expression and HNF1α and their J. M. 1998; PubMed Scopus Google Scholar). studies that the gene can be regulated by in sex-dependent expression by a mechanism STAT5b and O. M. Mol. Endocrinol. 2000; PubMed Scopus Google Scholar). and expression in adult female is to regulation by HNF3β and N. Park S.H. Waxman D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) as as by and T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the of these transcription factor in gene expression is is their in the of sex-specific liver gene of factors and interactions between GH-regulated and and be required to establish and maintain the and sexually dimorphic of gene expression. The the of GH-activated STAT5b the expression of CYP2C11 and regulation by transcription gene expression is to regulation by GH-activated STAT5b in a manner that is modulated by liver transcription factors that HNF3β and novel inhibitory between HNF3β and GH-activated STAT5b is The of these in the of for the sex-dependent regulation of CYP2C11 expression by plasma GH STAT5b was from a was from Cell HNF3β and the were from the was from for and for were by of and of for mouse STAT5b A. mouse H. of the rat GH receptor N. HNF1α of and of and and HNF3β New were from the The STAT5 reporter of a STAT5 and the HNF3 reporter were by M. of and of of the were by rat DNA as and into and sites of the luciferase reporter with the of of were for of for for and for were as to to to to and to were with a to to promoter reporter and was from by with and by in and of promoter the of of the at to in This sequence was in DNA from rat DNA promoter nucleotide were to the to the a of the and were as to to and and were into the sites of the luciferase reporter A reporter of the STAT5 into promoter was by of and were by DNA sequence adult and with rat rat were (13Waxman D.J. Ram P.A. Park S.H. Choi H.K. J. Biol. Chem. 1995; 270: 13262-13270Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). were from liver and at P.A. Park S.H. Choi H.K. Waxman D.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). HepG2 and cells were in and HepG2 cells were at a of in The cells were with Molecular complexes were as in the at a of to of a a of of of luciferase reporter of of of GH of STAT5b, and expression was in as for the cells were with rat GH for were Cell were by the cells in of for at and luciferase were a reporter assay and a luciferase activity were by activity to luciferase for luciferase were to between a were for the Cell were for and as and HepG2 cells were at and A of of DNA GH STAT5b, HNF3β expression and luciferase was as in the cells were with GH for were The cells were with and with of and The cell were in a for with and for at The were in and at were with protein assay with as a Cell extract was for in of and of Molecular was and for at by the of of STAT5b was of the DNA by HNF3β disruption was with the for to of the DNA The were for at a in STAT5 in the a The were to and a Molecular and was the DNA STAT5 from rat CYP2C11, as in STAT5 (13Waxman D.J. Ram P.A. Park S.H. Choi H.K. J. Biol. Chem. 1995; 270: 13262-13270Abstract Full Text Full Text PDF PubMed Scopus (213) Google site, to and were in the HNF3 binding to the STAT5 binding to of the to a STAT5 consensus as to HNF3 consensus in with the Cell were and with STAT5b as in the with with cell extract was for at in a of of of protein and of were by and was to the cell and for complexes were by a of with of protein at with and in of The were with and (13Waxman D.J. Ram P.A. Park S.H. Choi H.K. J. Biol. Chem. 1995; 270: 13262-13270Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). binding was by the from with HNF3β were in for at were in in and for at and at with in The in from of of the of were a and the of STAT5 consensus sites in the DNA and of is expressed in rat liver in a male-specific manner and is regulated by the pattern of pulsatile plasma GH stimulation the STAT5 consensus sites were in the 5′-flank of other rat including CYPs and which not to GH pulse regulation not the STAT5 sites functional in STAT5 were liver nuclear from adult male at the of a plasma GH pulse STAT5b is and nuclear H.K. Waxman D.J. Endocrinology. 2000; 141: 3245-3255Crossref PubMed Scopus (98) Google Scholar). the of a complex by the and and CYP4A2 STAT5 and These complexes were strongly by and were by and complex was formed with liver nuclear from female and and from of male between GH pulses STAT5b is and H.K. Waxman D.J. Endocrinology. 2000; 141: 3245-3255Crossref PubMed Scopus (98) Google Scholar). complexes of the mobility were formed by male liver nuclear with STAT5 and with of GH-treated cells with STAT5b and GH receptor and not These complexes were from the complex formed by STAT5a, which more and is STAT5b in liver S.H. Waxman D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In to the complex formed by and CYP4A2 STAT5 STAT5 formed a complex with male rat liver nuclear extract the of STAT5b protein in the complex of the STAT5 complex was male-specific and could be induced by of with a pulse of GH and was not induced by of with and of which activates liver STAT5 (13Waxman D.J. Ram P.A. Park S.H. Choi H.K. J. Biol. Chem. 1995; 270: 13262-13270Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). of the STAT5 binding STAT5 binding to the promoter of the sequence was effect the STAT5 is functional in reporter gene activity, luciferase reporter by the STAT5 were into HepG2 cells with expression for GH receptor and STAT5b. GH a in luciferase reporter activity by the STAT5 but not the STAT5 sequence a STAT5 This was in but not reporter activity was by by a of the GH effect in cells with the STAT5b tyrosine phosphorylation We that GH-activated STAT5b to the STAT5 of in a transcriptionally the GH transcriptional activity, luciferase reporter of from to of DNA and to to the transcription These were into HepG2 cells with GH receptor and STAT5b to establish a GH signaling promoter expression in the of GH from to the reporter A in promoter activity was with with the of a between and a of a between and A. H. Mode A. C. J.A. DNA Cell Biol. PubMed Scopus Google Scholar). promoter activity was by by GH in at of promoter sequence The inhibition of transcription that the STAT5 at −1150 to is not required for inhibition of promoter activity was in cells with the STAT5b tyrosine phosphorylation not We the inhibitory effect of STAT5b promoter activity can be modulated by of more transcription of the of the liver factors HNF3β, and promoter activity a by HNF1α and HNF3β A and promoter activity the other factors including and effect not activation of the promoter by HNF1α was with activation by HNF3β was seen with that the to promoter to and to of the promoter by HNF3β was seen with and was to with promoter activity was by of the in This was reversed with and was reversed with the a of HNF3β between and at promoter to to to and to contribute to of of these also the to STAT5b inhibition of promoter activity We HNF1α and HNF3β can with other with STAT5b to regulate promoter activity. of HNF3β with HNF1α transcription of of the and in a manner with the activation patterns by the factors and of that STAT5b and GH receptor were GH promoter activity but effect promoter activity The of HNF1α to the of HNF3β and STAT5b but not the to which promoter activity was inhibited by GH-activated STAT5b inhibition in the of inhibition in This that HNF1α with HNF3β to the and inhibition of The mechanism STAT5b promoter activity was by the of STAT5b HNF3β DNA binding activity. a that a consensus HNF3 to and the STAT5 to to complex and complex in HepG2 cell complexes were with cell and both were in by of not protein, as by the inhibitory effect of and complex This inhibition was by in mobility of the protein complex and in The of HNF3 in complex is by the in complex of the HNF3 binding and the level of proteins in cells with HepG2 cells cells were to investigate the of GH-activated STAT5b HNF3β binding to the promoter cells were with HNF3β, with STAT5b and GH with factors in of HNF3β by not the of complex in cell not with STAT5b and stimulation with the complex was by a DNA complex of mobility with STAT5b This effect of STAT5b was more in the HNF3 and In STAT5b effect complex in the of STAT5b not of STAT5b with HNF3β inhibited of both the STAT5-DNA complex and the complex in a manner and not This that factor to the HNF3β and GH-activated STAT5b the STAT5 and HNF3 consensus binding sites the with the binding activity seen in the of GH-activated STAT5b in from between STAT5b and HNF3β for binding to their of the STAT5 site, leading to the of STAT5b binding seen the STAT5 and not HNF3β DNA binding activity in cells with STAT5b This that STAT5b and HNF3β in inhibitory manner that is to their binding to sites the GH-activated STAT5b HNF3β transcriptional activity a reporter that not STAT5 binding HepG2 cells were with HNF3β and a luciferase reporter by of HNF3 binding site, from the gene H. Kelly S. Mol. Biol. PubMed Scopus Google Scholar). This reporter is by and HNF3β but not by which can to a of promoter in with HNF3β Mol. Biol. 1996; PubMed Scopus Google Scholar). STAT5b inhibited transcription of the reporter in a GH and manner the of STAT5 binding the expression of STAT5b protein and DNA binding activity these that the and inhibition of promoter activity from a of HNF3β DNA binding activity a of the inhibition by GH-activated STAT5b of promoter activity is to inhibition by STAT5b of the HNF3β in the HepG2 cells in studies We the inhibitory interactions between HNF3β and STAT5b as by the of HNF3β GH-activated STAT5b transcriptional activity. STAT5b activity was in HepG2 cells with GH receptor and a STAT5 reporter of a STAT5 from the S.J. M. J. PubMed Scopus Google Scholar). in GH a in reporter activity. HNF3β inhibited transcriptional in a the of HNF3 binding sites in the In of liver transcription effect STAT5b reporter activity not the mechanism for inhibitory effect of HNF3β, HNF3β with STAT5b that HNF3β inhibited STAT5b as in cells by the of STAT5b to the of STAT5b a in STAT5b tyrosine phosphorylation was by HNF3β inhibition of STAT5b tyrosine phosphorylation was also in HepG2 as by and This inhibition in a in STAT5 DNA binding activity, by a HNF3β thus transcription by a mechanism that the GH STAT5b tyrosine phosphorylation The the of STAT5b and of transcription factors in the and expression STAT5 binding sites were identified in male-specific liver and in the the binding was to reporter activity to a These the of STAT5b in the male-specific profile of liver gene expression that was the repeated tyrosine phosphorylation and nuclear translocation of liver STAT5b in to male plasma GH pulse (13Waxman D.J. Ram P.A. Park S.H. Choi H.K. J. Biol. Chem. 1995; 270: 13262-13270Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 15Choi H.K. Waxman D.J. Endocrinology. 2000; 141: 3245-3255Crossref PubMed Scopus (98) Google Scholar, 16Tannenbaum G.S. Choi H.K. Gurd W. Waxman D.J. Endocrinology. 2001; 142: 4599-4606Crossref PubMed Scopus (59) Google Scholar) and the of male-specific expression in Park S.H. Ram P.A. Waxman D.J. S. A. PubMed Scopus Google Scholar, S.H. Waxman D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. M. S. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). of the STAT5b responsiveness of the promoter a and in promoter activity This effect of STAT5b was to inhibitory with the liver transcription factor HNF3β, with can strongly promoter activity These the complex interrelationship between STAT5b and transcription factors that contribute to the transcriptional activity of GH-regulated liver genes. the inhibitory of STAT5b transcription could contribute to the of the gene in female rat liver, STAT5b is activated in a nearly continuous at a low level (14Choi H.K. Waxman D.J. Endocrinology. 1999; 140: 5126-5135Crossref PubMed Scopus (75) Google Scholar). transcription factors in a complex with STAT5b M. Mol. Endocrinol. 2000; PubMed Scopus Google Scholar). in with STAT5b, activates the in turn, expression of HNF3β and This to the expression of GH-inducible with HNF3β and GH-regulated the by binding to promoter sites N. Park S.H. Waxman D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, O. H. Gustafsson J. Mode A. S. A. PubMed Scopus Google Scholar), and HNF3β and but not CYP2C11 that STAT5b can expression the of GH pulse-activated STAT5b such that the of STAT5b at the of GH pulse H.K. Waxman D.J. Endocrinology. 2000; 141: 3245-3255Crossref PubMed Scopus (98) Google Scholar, 16Tannenbaum G.S. Choi H.K. Gurd W. Waxman D.J. Endocrinology. 2001; 142: 4599-4606Crossref PubMed Scopus (59) Google Scholar) could as a to and the This is not the of STAT5b evidenced by the of male-specific liver CYPexpression in Park S.H. Ram P.A. Waxman D.J. S. A. PubMed Scopus Google Scholar). with a of STAT5b, is that the of active, nuclear STAT5b in male rat a plasma GH pulse directly stimulate By contrast, in the of a low level of nuclear STAT5b as a signal by the gene activation potential of to nuclear STAT5b the level required to in male but not female liver. This activation with the of which the promoter and can the inhibitory of STAT5b transcription in the studies of the HepG2 cells were with GH a that the female plasma GH to stimulate a pulsatile pattern of STAT5b activation in HepG2 cells were by the of STAT5b in cell This a of the promoter can be by STAT5b the is activated in a pulsatile as in male rat HNF3β and STAT5b were to inhibitory as by studies the interactions of these factors a promoter that HNF3β and STAT5 binding that DNA binding is not required for The inhibitory between HNF3β and STAT5b could protein interactions between the transcription such was in Park and J. In with the inhibition of STAT5b transcriptional activity by HNF3β was to a novel mechanism HNF3β STAT5b activation at the level of STAT5b tyrosine phosphorylation by STAT5b DNA binding for effect of HNF3β STAT5b activation include expression of a of GH kinase such as a N. T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) a protein, of which can strongly GH signaling to STAT5b P.A. Waxman D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. D.J. N. Mol. Endocrinol. 1999; PubMed Google Scholar). The that STAT5b can HNF3β transcriptional activity in the of a STAT5 that STAT5b and transcription in promoter of STAT5 sites N. Park S.H. Waxman D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The mechanism for inhibitory effect of STAT5b is of STAT5b with other transcription including the nuclear receptor inhibition is by the transcriptional of the nuclear receptor Waxman D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Waxman D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and the factor which is inhibited by STAT5b by for the Endocrinol. 2000; Google Scholar). inhibitory of the of to promoter activity in cells with H. Biochem. 2000; PubMed Scopus Google is not GH-activated STAT5b is to that inhibition and expression. STAT5b gene expression by transcriptionally the consensus sequence to STAT5 that their to a STAT5 complex M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. Mol. Biol. 1999; 19: PubMed Scopus Google Scholar). STAT5 functional between STAT5 binding sites by the level of of both sites a level required for activity. In the the STAT5 that −1150 to is flanked by sites at to and at to with a between the STAT5 and of the HNF3 consensus at to −1150 and at and the sites and from the STAT5 the inhibitory between HNF3β and STAT5b not factor as the close the of the HNF3β and STAT5 sites in the could to the inhibitory by for STAT5b DNA of STAT5b as in a GH male be required to the inhibitory of HNF3β, leading to STAT5b activation of gene expression. This activation could be by the STAT5 at −1150 to identified in the in with the STAT5 sites in the promoter in gene also be STAT5b is to STAT5 that as but not the STAT5 consensus sequence S. S. J. Mol. Biol. 2000; PubMed Scopus Google Scholar). STAT5b plays in expression of male-expressed other liver gene as in the mouse studies Park S.H. Ram P.A. Waxman D.J. S. A. PubMed Scopus Google Scholar, S.H. Waxman D.J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), factors to be required to the male-specific pattern of gene expression. This is by the rapid activation of liver STAT5 in a of GH (13Waxman D.J. Ram P.A. Park S.H. Choi H.K. J. Biol. Chem. 1995; 270: 13262-13270Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, P.A. Park S.H. Choi H.K. Waxman D.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), in to the repeated pulsatile GH stimulation at that is required to male-specific liver expression in the (8Sundseth S.S. Alberta J.A. Waxman D.J. J. Biol. Chem. 1992; 267: 3907-3914Abstract Full Text PDF PubMed Google Scholar, P.G. Mode A. Strom A. Gustafsson J.A. Suppl. Google Scholar). A of the for factors is the effect with the STAT5 in the and that of the in A. J. 1998; PubMed Scopus Google Scholar). activation of STAT5b in pulses of GH for is not to gene expression, to a for liver factors that in H.K. Waxman D.J. Endocrinology. 2000; 141: 3245-3255Crossref PubMed Scopus (98) Google Scholar). is required to these factors and to establish the and GH and sexually dimorphic patterns the sex-dependent expression of and other liver genes. We A. H. N. M. and for and

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