Key points are not available for this paper at this time.
Insulin inhibits the expression of multiple genes in the liver containing an insulin response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein kinase B (PKB) mediates this effect of insulin. Genetic studies inCaenorhabditis elegans indicate that daf-16, aforkhead/winged-helix transcription factor, is a major target of the insulin receptor-PKB signaling pathway. FKHR, a human homologue of daf-16, contains three PKB sites and is expressed in the liver. Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates insulin-like growth factor-binding protein-1 promoter activity through an IRS, and introduction of IRSs confers this effect on a heterologous promoter. Insulin disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by PKB is necessary and sufficient to mediate this effect. Antisense studies indicate that FKHR contributes to basal promoter function and is required to mediate effects of insulin and PKB on promoter activity via an IRS. To our knowledge, these results provide the first report that FKHR stimulates promoter activity through an IRS and that phosphorylation of FKHR by PKB mediates effects of insulin on gene expression. Signaling to FKHR-related forkheadproteins via PKB may provide an evolutionarily conserved mechanism by which insulin and related factors regulate gene expression. Insulin inhibits the expression of multiple genes in the liver containing an insulin response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein kinase B (PKB) mediates this effect of insulin. Genetic studies inCaenorhabditis elegans indicate that daf-16, aforkhead/winged-helix transcription factor, is a major target of the insulin receptor-PKB signaling pathway. FKHR, a human homologue of daf-16, contains three PKB sites and is expressed in the liver. Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates insulin-like growth factor-binding protein-1 promoter activity through an IRS, and introduction of IRSs confers this effect on a heterologous promoter. Insulin disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by PKB is necessary and sufficient to mediate this effect. Antisense studies indicate that FKHR contributes to basal promoter function and is required to mediate effects of insulin and PKB on promoter activity via an IRS. To our knowledge, these results provide the first report that FKHR stimulates promoter activity through an IRS and that phosphorylation of FKHR by PKB mediates effects of insulin on gene expression. Signaling to FKHR-related forkheadproteins via PKB may provide an evolutionarily conserved mechanism by which insulin and related factors regulate gene expression. Insulin exerts important effects on gene expression in multiple tissues (1O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (438) Google Scholar). In the liver, insulin suppresses the expression of a number of genes that contain a conserved insulin response sequence (IRS) 1The abbreviations used are: IRS, insulin response element; IGFBP-1, insulin-like growth factor-binding protein-1; PEPCK, phosphoenolpyruvate carboxykinase; apoCIII, apolipoprotein CIII; PKB, protein kinase B; PI3K, phosphatidylinositol 3′-kinase; HNF-3, hepatocyte nuclear factor-3; Hyd, any hydrophobic amino acid; CMV, cytomegalovirus; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MAPK, mitogen-activated protein kinase; MAPKK1, mitogen-activated protein kinase kinase-1; RT-PCR, reverse transcription-polymerase chain reaction; bp, base pair(s); kb, kilobase(s) (CAAAA(C/T)AA), including insulin-like growth factor-binding protein-1 (IGFBP-1), apolipoprotein CIII (apoCIII), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (2Goswami R. Lacson R. Yang E. Sam R. 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HepG2 cells to and in with with and to a containing of the FKHR including of from and by a by RT-PCR, with and reverse to of of at at and at by at Specific to the of FKHR including downstream from the and of FKHR including downstream from the and M. S. K. 1998; 47: PubMed Scopus Google Scholar) and and M. S. K. 1998; 47: PubMed Scopus Google Scholar). by and with with and and and and with an in the of at To FKHR may the expression of genes that by insulin through an IRS, we first studies in HepG2 cells with a gene containing the IGFBP-1 promoter and a expression by the promoter. in with an FKHR expression stimulates the IGFBP-1 promoter and activity in a of indicating that this effect is this effect of FKHR is mediated through an IRS. IGFBP-1 promoter contains IRSs to the and and is sufficient to mediate effects of insulin on promoter activity A. Morris S.L. Powell D.R. J. Biol. Chem. 1993; 268: 17063-17068Abstract Full Text PDF PubMed Google Scholar, S. A. S. A. Unterman J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). in of and disrupts the of insulin to and the of FKHR to promoter the of is sufficient to mediate effects of insulin and FKHR on promoter of a base disrupts the effects of insulin and FKHR on promoter that insulin and FKHR exert their effects in a from its to with mediates effects of insulin and FKHR on promoter a sequence at this is not in an of IRSs from the kinase promoter is sufficient to effects of insulin and FKHR on promoter In sequence of containing sites at this is not these results indicate that FKHR, exerts effects on promoter activity through an effects of insulin and cells with gene containing the IGFBP-1 promoter where have and To effects of insulin on promoter cells with of including of gene with insulin to and of To the effects of FKHR on promoter cells with of including of gene of a FKHR expression and of and in to of effects of insulin and FKHR on promoter activity expressed the to and reported the in a HepG2 cells with gene containing the IGFBP-1 promoter where have and To effects of insulin on promoter cells with of including of gene with insulin to and of To the effects of FKHR on promoter cells with of including of gene of a FKHR expression and of and in to of effects of insulin and FKHR on promoter activity expressed the to and reported the To the effects of insulin and FKHR on promoter activity mediated through an IRS with sequence we a of gene where a IRS at a in which the of insulin to promoter activity the of FKHR to promoter the the of insulin to and the of FKHR to promoter activity in this of gene which is that contain the IRS in the PEPCK gene and to insulin and FKHR, that FKHR may the activity of the PEPCK and through related these results indicate that FKHR and the mediating the effects of insulin and PKB on promoter activity with the IRS with sequence and the that FKHR related may to the of IGFBP-1 promoter activity through an effects of insulin and cells with of including of a gene containing a IRS of base multiple of FKHR expression and of with insulin to and of in a HepG2 cells with of including of a gene containing a IRS of base multiple of FKHR expression and of with insulin to and of To this we first FKHR is expressed in HepG2 in with FKHR the of an in from HepG2 to results in human liver M. S. K. 1998; 47: PubMed Scopus Google Scholar). in with the of FKHR of and bp, and FKHR and of these with the reported sequence the FKHR M. S. K. 1998; 47: PubMed Scopus Google Scholar), that FKHR is expressed in HepG2 To FKHR may to the of IGFBP-1 promoter activity in HepG2 we studies with a that of the and the first of the FKHR in an in this disrupts the of FKHR to promoter activity through an IRS not with the of to promoter function through a sequence at the This that this disrupts IRS-dependent transactivation by FKHR studies with this that it the activity of the IGFBP-1 promoter activity in a the of expressed by a indicating that this effect is not in the of FKHR to activity of the IGFBP-1 promoter is and the of and is sufficient to the IGFBP-1 promoter to by FKHR an of IRSs to the promoter is sufficient to a effect of FKHR on the activity of this heterologous promoter. results the that FKHR related to basal promoter activity through an IRS-dependent mechanism. used this to FKHR may be required the of insulin and PKB to basal promoter activity through an IRS. studies have that insulin inhibits IGFBP-1 promoter activity through an IRS (2Goswami R. Lacson R. Yang E. Sam R. Unterman T. Endocrinology. 1994; 134: 2531-2539Crossref Scopus (95) Google Scholar, 3Suwanickul A. Morris S.L. Powell D.R. J. Biol. Chem. 1993; 268: 17063-17068Abstract Full Text PDF PubMed Google Scholar) and that PKB is necessary and sufficient to mediate this effect of insulin S. A. S. A. Unterman J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). in expression of FKHR the activity of the IGFBP-1 promoter and is in promoter function by insulin PKB in the of FKHR with gene containing an of IRSs from the kinase promoter results In FKHR promoter activity and is inhibitory effect of insulin PKB on promoter function in with FKHR studies to FKHR disrupts the of insulin and PKB to promoter activity through an IRS disrupts effects of insulin and PKB in HepG2 in FKHR and PKB promoter activity to a in a gene containing a IRS and is effect of insulin PKB on promoter activity in with FKHR with results with containing an IRS In we that insulin and PKB promoter activity the IRS is by an and that FKHR not this effect of insulin PKB This that FKHR disrupts the of insulin and PKB to promoter activity through an IRS effects of insulin and PKB on promoter activity in HepG2 these results indicate that FKHR, a related factor, is required the of insulin and PKB to promoter activity through an IRS and the that insulin and PKB may promoter activity by IRS-dependent transactivation by on these and studies indicating that PKB is necessary and sufficient insulin to promoter activity through an IRS S. A. S. A. Unterman J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), we insulin inhibits promoter activity and PKB mediates this effect of insulin. with of a FKHR expression with a gene containing a IRS results in a of promoter activity in insulin inhibits promoter activity by This effect of insulin is not by with a of the of kinase kinase D.R. A. Cohen P. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), with a of indicating that it is not mediated through the pathway. In with a of J. Biol. 1994; PubMed Scopus Google Scholar), and with a of the of this effect of insulin indicating that insulin suppresses promoter activity through a mechanism. which the of kinase downstream from Curr. Opin. Biol. 1997; PubMed Scopus Google Scholar), not this effect of insulin. In expression of a of PKB the effect of PKB inhibits promoter the effect of insulin. these results indicate that PKB is necessary and sufficient to mediate the effect of insulin on promoter FKHR contains three PKB phosphorylation sites and and we have that PKB of these sites in and in cells S. Unterman Cohen P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). To the phosphorylation of these sites is required insulin PKB to transactivation by FKHR, we first and to and and of these to not the of FKHR to promoter activity of and not FKHR the of insulin and PKB to promoter activity studies with the that of not the of insulin and PKB to promoter function not indicate that phosphorylation of Ser-256 is required the of insulin and PKB to IRS-dependent transactivation by To the introduction of a at these sites is sufficient to the of FKHR to promoter we to in of Ser-256 to disrupts IRS-dependent transactivation by In and not the of FKHR to promoter activity through an IRS-dependent mechanism studies with the that of Ser-256 not to disrupts transactivation by FKHR these results indicate that phosphorylation of Ser-256 by PKB and the introduction of a at this is necessary and sufficient to IRS-dependent transactivation by In the we to FKHR, a of the of transcription factors, may to the of gene expression by insulin and provide a target mediating effects of insulin and PKB on gene expression through a conserved IRS. 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In the we used and expression and of signaling to that insulin inhibits promoter activity through a mechanism mediated by on studies where and to a amino acid that is not to phosphorylation by to which a we that phosphorylation of Ser-256 by PKB is necessary and sufficient insulin to IRS-dependent transactivation by to be the phosphorylation of functions of in Ser-256 is in the of the of with that this of the a the of target sites where it may with and E. Nature. 1993; PubMed Scopus Google Scholar). is to that the phosphorylation of Ser-256 and the introduction of a at this the of this and in and studies with nuclear have to a an IRS is disrupted by insulin (2Goswami R. Lacson R. Yang E. Sam R. Unterman T. Endocrinology. 1994; 134: 2531-2539Crossref Scopus (95) Google Scholar, 3Suwanickul A. Morris S.L. Powell D.R. J. Biol. Chem. 1993; 268: 17063-17068Abstract Full Text PDF PubMed Google Scholar, S. O'Brien R.M. E. Granner D.K. R. J. Biol. 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