C/EBP and the Control of Phosphoenolpyruvate Carboxykinase Gene Transcription in the Liver

CAAT/enhancer-binding protein phosphoenolpyruvate carboxykinase cAMP regulatory element nuclear factor I cAMP regulatory element-binding protein CREB-binding protein glucocorticoid response unit hepatic nuclear factor I insulin regulatory element peroxisome proliferator-activated receptor catalytic subunit of PKA protein kinase C. In 1989, shortly after the discovery of CAAT/enhancer-binding protein (C/EBP)1 and in a period before it was clear that there was more than one form of C/EBP, McKnight et al. (1McKnight S.L. Lane M.D. Glueckshon-Waelch S. Genes Dev. 1989; 3: 2021-2024Crossref PubMed Scopus (195) Google Scholar) published a review entitled: “Is C/EBP a Central Regulator of Energy Metabolism?” This prediction of a critical metabolic role for this transcription factor was based on the very slim evidence that C/EBP was involved in the transcription of a number of metabolically important genes such as 422/aP2, phosphoenolpyruvate carboxykinase (PEPCK), and fatty acid synthase, in addition to its role in the differentiation of adipocytes (2Yeh W.-C. Bierer B. McKnight S.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11086-11090Crossref PubMed Scopus (195) Google Scholar, 3Cristy R.J. Yang V.W. Ntambi J.M. Geiman D.E. Landschulz W.H. Freidman A.D. Kelly J.T. Lane M.D. Genes Dev. 1989; 3: 1235-1323Google Scholar). Over the decade since this article was published, the prediction has proven to be remarkably accurate. C/EBP is now known to comprise a gene family with a number of closely related members, the biology of which has been detailed in the first minireview in this series by Lekstrom-Himes and Xanthopoulos (4Lekstrom-Himes J. Xanthopoulos K.G. J. Biol. Chem. 1998; 273: 28545-28548Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar). These C/EBP isoforms can stimulate or inhibit transcription from a growing list of genes in a variety of tissues in animals as diverse as chickens and rats. One of the critical aspects of the biology of C/EBP that has emerged over the past 10 years is the key role that members of the family of transcription factors play in both the development and maintenance of metabolically important processes (1McKnight S.L. Lane M.D. Glueckshon-Waelch S. Genes Dev. 1989; 3: 2021-2024Crossref PubMed Scopus (195) Google Scholar, 5Darlington G.J. Wang N. Hanson R.W. Curr. Opin. Genet. Dev. 1995; 5: 565-570Crossref PubMed Scopus (115) Google Scholar, 6Croniger C. Trus M. Lysek S.K. Cohen H. Liu Y. Darlington G.J. Poli V. Hanson R.W. Reshef L. J. Biol. Chem. 1997; 272: 26306-26312Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). This review will focus on the effects of C/EBP isoforms on the control of transcription of the gene for the key gluconeogenic enzyme PEPCK (GTP) (EC 4.1.1.32) as a model for its regulation of other genes that code for enzymes of metabolic importance. The transcriptional control of the gene for the cytosolic form of PEPCK from the rat (7Hanson R.W. Patel Y.M. Meister A. P-enolpyruvate Carboxykinase: the Gene and the Enzyme. Advances in Enzymology. 69. John Wiley & Sons, Inc., New York1994: 203-281Google Scholar, 8O’Brien R.M. Lucas P.C. Yamasaki T. Noisin E.L. Granner D.K. J. Biol. Chem. 1994; 269: 30419-30428Abstract Full Text PDF PubMed Google Scholar, 9Quinn P.G. Granner D.L. Mol. Cell. Biol. 1990; 10: 3357-3364Crossref PubMed Scopus (69) Google Scholar) and chicken (10Savon S. Hakimi P. Hanson R.W. Biol. Neonate. 1993; 64: 62-68Crossref PubMed Scopus (23) Google Scholar, 11Savon S.P. Hakimi P. Crawford D.R. Klemm D.J. Gurney A.L. Hanson R.W. J. Nutr. 1997; 127: 276-285Crossref PubMed Scopus (7) Google Scholar) has been extensively studied. The promoter regulatory region of the gene from the rat is shown in Fig. 1. Because the sequence of the promoter for the PEPCK gene from the mouse, rat, and human has been remarkably conserved (greater than 95% sequence identity), it is reasonable to assume that the pattern of transcriptional regulation noted from studies with the PEPCK gene promoter from rodents is characteristic of the control in most mammalian species. The PEPCK gene promoter contains several critical regions of transcription factor binding that are required for the regulation of PEPCK gene transcription. This region contains a cAMP regulatory element (CRE) (−91 to −84), which is about 60 base pairs 5′ from the TATA box (−29 to −23) and is immediately adjacent to a nuclear factor 1 (NFI)-binding site (−116 to −104). The CRE has been shown to bind members of the leucine zipper family of transcription factors, including C/EBPα (12Roesler W.J. Vandenbark G.R. Hanson R.W. J. Biol. Chem. 1989; 264: 9657-9664Abstract Full Text PDF PubMed Google Scholar, 13Trus M. Benvenisty N. Cohen H. Reshef L. Mol. Cell. Biol. 1990; 10: 2418-2422Crossref PubMed Scopus (32) Google Scholar), C/EBPβ (14Park E.A. Gurney A.L. Nizielski S.E. Hakimi P. Cao Z. Moorman A. Hanson R.W. J. Biol. Chem. 1993; 267: 613-619Abstract Full Text PDF Google Scholar), D-binding protein (15Roesler W.J. McFie P.J. Dauvin C. J. Biol. Chem. 1992; 267: 21235-21243Abstract Full Text PDF PubMed Google Scholar), AP-1 (16Gurney A.L. Park E.A. Giralt M. Liu J. Hanson R.W. J. Biol. Chem. 1992; 267: 18133-18139Abstract Full Text PDF PubMed Google Scholar), cAMP regulatory element-binding protein (CREB) (17Quinn P.G. J. Biol. Chem. 1993; 268: 16999-17009Abstract Full Text PDF PubMed Google Scholar), cAMP regulatory element modulator (CREM) (18Goraya T.Y. Kessler S.P. Stanton P.W., H.R. Sen G.C. J. Biol. Chem. 1995; 270: 19078-19085Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar), and Jun/Jun homodimers (16Gurney A.L. Park E.A. Giralt M. Liu J. Hanson R.W. J. Biol. Chem. 1992; 267: 18133-18139Abstract Full Text PDF PubMed Google Scholar). The CRE is required for the full induction of transcription from the PEPCK gene promoter by cAMP (19Liu J. Park E.A. Gurney A.L. Roesler W.J. Hanson R.W. J. Biol. Chem. 1991; 266: 19095-19102Abstract Full Text PDF PubMed Google Scholar). Recently, we have demonstrated that NFI inhibits transcription from the PEPCK gene promoter and suggested that an interaction between NFI and CREB-binding protein (CBP) is involved in the control of the basal level of transcription of the PEPCK gene in the liver (20Crawford D.R. Leahy P. Hu C.Y. Gronostajski R. Grossman G. Woods J. Hakimi P. Roesler W.J. Hanson R.W. J. Biol. Chem. 1998; 273: 13387-13390Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). This region contains an hepatic nuclear factor 1 (HNF-1) regulatory element (−190 to −185), which, despite its name, is critical for the expression of the PEPCK gene in the kidney of transgenic mice. There is a C/EBP-binding domain (−234 to −235), termed P3(I), which is required for the liver-specific expression of the PEPCK gene (21Patel Y.M. Yun J.S. Liu J. McGrane M.M. Hanson R.W. J. Biol. Chem. 1994; 269: 5619-5628Abstract Full Text PDF PubMed Google Scholar); members of the C/EBP family are the only transcription factors that are known to bind to the P3(I) site. This site is involved in the cAMP stimulation of transcription from the PEPCK gene promoter since its deletion results in a 60–70% drop in expression from the promoter in the presence of cAMP in both hepatoma cells (19Liu J. Park E.A. Gurney A.L. Roesler W.J. Hanson R.W. J. Biol. Chem. 1991; 266: 19095-19102Abstract Full Text PDF PubMed Google Scholar) and in transgenic mice (21Patel Y.M. Yun J.S. Liu J. McGrane M.M. Hanson R.W. J. Biol. Chem. 1994; 269: 5619-5628Abstract Full Text PDF PubMed Google Scholar). C/EBP also binds to the P4 site (−282 to −274) (12Roesler W.J. Vandenbark G.R. Hanson R.W. J. Biol. Chem. 1989; 264: 9657-9664Abstract Full Text PDF PubMed Google Scholar). A thyroid hormone regulatory element is located at −332 to −316 of the PEPCK gene promoter (22Giralt M. Park A.E. Gurney A. Liu J.S. Hakimi P. Hanson R.W. J. Biol. Chem. 1991; 266: 21991-21996Abstract Full Text PDF PubMed Google Scholar, 23Park E.A. Song S. Oliver M. Roesler W.J. Biochem. J. 1996; 322: 343-348Crossref Scopus (33) Google Scholar). This region contains the glucocorticoid response unit (GRU) composed of two glucocorticoid regulatory elements, three accessory factor-binding sites, and a CRE (24Scott D.K. Stromstedt P.-E. Wang J.-C. Granner D.K. Mol. Endocrinol. 1998; 12: 482-491Crossref PubMed Scopus (65) Google Scholar). The entire element lies between −321 and −455 of the PEPCK gene promoter (24Scott D.K. Stromstedt P.-E. Wang J.-C. Granner D.K. Mol. Endocrinol. 1998; 12: 482-491Crossref PubMed Scopus (65) Google Scholar). The GRU also contains an insulin regulatory element (IRE) (−414 to −400), which lies within the AF2 domain of the GRU (the AF2 site binds C/EBP and HNF-3) and is responsible for about 50% of the inhibitory effect of insulin on hepatic PEPCK gene transcription (25O’Brien R.M. Lucas P.C. Forest C.D. Magnunson M.A. Granner D.K. Science. 1990; 249: 533-537Crossref PubMed Scopus (289) Google Scholar). However, deletion of the IRE completely inhibits the diabetes-induced increase of PEPCK gene transcription in the liver of transgenic mice and renders the PEPCK gene promoter refractory to induction by glucocorticoids (26Friedman J.E. Yun J.S. Patel Y.M. McGrane M.M. Hanson R.W. J. Biol. Chem. 1993; 268: 12952-12957Abstract Full Text PDF PubMed Google Scholar). This region contains a PPARγ regulatory element (−999 to −987), which is required for the adipose tissue-specific expression of the PEPCK gene in both cultured adipocytes (27Tontonoz P. Hu E. Devine J. Beale E.G. Spiegelman B.M. Mol. Cell. Biol. 1995; 15: 351-357Crossref PubMed Google Scholar) and in adipose tissue of transgenic mice in which the region containing the PPARγ element has been deleted (28Short M.K. Clouthier D.E. Schaefer I.M. Hammer R.E. Magnunson M.A. Beale E.G. Mol. Cell. Biol. 1992; 12: 1007-1020Crossref PubMed Scopus (101) Google Scholar). Of the C/EBP isoforms, only C/EBPα (6Croniger C. Trus M. Lysek S.K. Cohen H. Liu Y. Darlington G.J. Poli V. Hanson R.W. Reshef L. J. Biol. Chem. 1997; 272: 26306-26312Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 23Park E.A. Song S. Oliver M. Roesler W.J. Biochem. J. 1996; 322: 343-348Crossref Scopus (33) Google Scholar, 29Wang N.D. Finegold M. Bradley A. Ou C.N. Abdelsayed S.V. Wilde M.D. Taylor L.R. Wilson D.R. Darlington G.J. Science. 1995; 269: 1108-1112Crossref PubMed Scopus (835) Google Scholar), C/EBPβ (14Park E.A. Gurney A.L. Nizielski S.E. Hakimi P. Cao Z. Moorman A. Hanson R.W. J. Biol. Chem. 1993; 267: 613-619Abstract Full Text PDF Google Scholar), and D-binding protein (15Roesler W.J. McFie P.J. Dauvin C. J. Biol. Chem. 1992; 267: 21235-21243Abstract Full Text PDF PubMed Google Scholar) have been implicated in the control of PEPCK gene transcription; all three of these isoforms of C/EBP bind to the PEPCK gene promoter and can stimulate transcription from the promoter when transfected into hepatoma cells. It is likely that these three transcription factors, either individually or in combination, regulate PEPCK gene transcription in the liver. Wang et al. (29Wang N.D. Finegold M. Bradley A. Ou C.N. Abdelsayed S.V. Wilde M.D. Taylor L.R. Wilson D.R. Darlington G.J. Science. 1995; 269: 1108-1112Crossref PubMed Scopus (835) Google Scholar) partially resolved the issue of which isoform of C/EBP controls the development of hepatic PEPCK gene transcription when they reported that PEPCK and glucose 6-phosphatase mRNAs were absent in the livers of mice with a deletion in the gene for C/EBPα (C/EBPα−/− mice). Subsequently, Flodby et al. (30Flodby P. Barlow C. H. L. Xanthopoulos K.G. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrated that mice also have The of genes expression is by a deletion in the gene for C/EBPα has been to it is clear from the that a number of these genes are involved in metabolic G.J. Wang N. Hanson R.W. Curr. Opin. Genet. Dev. 1995; 5: 565-570Crossref PubMed Scopus (115) Google Scholar). These enzymes involved in and fatty acid that are in the of mice have hepatic at is in the and in the of PEPCK and glucose they glucose to glucose in the both and adipose tissues also to (29Wang N.D. Finegold M. Bradley A. Ou C.N. Abdelsayed S.V. Wilde M.D. Taylor L.R. Wilson D.R. Darlington G.J. Science. 1995; 269: 1108-1112Crossref PubMed Scopus (835) Google Scholar). The of cAMP to mice at of in a induction of PEPCK in the liver of the control a increase in the level of C/EBPβ in the livers of the mice (6Croniger C. Trus M. Lysek S.K. Cohen H. Liu Y. Darlington G.J. Poli V. Hanson R.W. Reshef L. J. Biol. Chem. 1997; 272: 26306-26312Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). It is that C/EBPβ the of PEPCK gene transcription in the of The pattern of expression of the isoforms of C/EBP be critical for the of gene transcription in the liver. In studies from we have shown that mice past of and R. that the at one for C/EBPα be in the to that development The role of C/EBPα in transcription of the PEPCK gene was first demonstrated by Liu et al. (19Liu J. Park E.A. Gurney A.L. Roesler W.J. Hanson R.W. J. Biol. Chem. 1991; 266: 19095-19102Abstract Full Text PDF PubMed Google Scholar). reported that a PEPCK gene in which the CRE has been by the P3(I) site binds only is as to the catalytic subunit of PKA as the PEPCK gene Recently, Roesler et al. W.J. Park E.A. McFie P.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrated that C/EBPα can for in PEPCK gene transcription and the C/EBPα domain to a region between and In Roesler et al. W.J. C. McFie P.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) also reported that a of when transfected into hepatoma induction of transcription from the PEPCK gene promoter by the domain of C/EBPα was required for its effect on PEPCK gene transcription in hepatoma cells was required in that there is an interaction between C/EBP and other factors, which are critical for the full effect of C/EBPα on PEPCK gene transcription. A in the effects of a deletion in the gene for C/EBPα in mice is the of the deletion in the et al. B. Mol. Cell. Biol. 1997; PubMed Google Scholar) a of C/EBPα the The was to the livers of mice containing the gene for C/EBPα by sites, a the The hepatic expression of the genes for both C/EBPα and PEPCK was by in the livers of these that C/EBPα is required for the basal of PEPCK in the livers of mice. It is that this for C/EBPα be for by C/EBPβ or other C/EBP isoforms, which are in the liver of for a deletion in the gene for C/EBPβ were to the effects of C/EBPβ on the et al. L. P. A. E. C. S. G. L. R. A. G. Poli V. J. 1995; PubMed Scopus Google Scholar) reported that the mice a to animals that they have and these with the the mice of glucose L. P. A. E. C. S. G. L. R. A. G. Poli V. J. 1995; PubMed Scopus Google Scholar). However, both et al. L. P. A. E. C. S. G. L. R. A. G. Poli V. J. 1995; PubMed Scopus Google Scholar) and et al. T. S. M. N. N. H. S. N. T. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar) noted a to the of mice for a deletion in the gene for the number of mice was at of In a we reported that there are two noted with the mice (6Croniger C. Trus M. Lysek S.K. Cohen H. Liu Y. Darlington G.J. Poli V. Hanson R.W. Reshef L. J. Biol. Chem. 1997; 272: 26306-26312Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). with A about of and of with a the other of the with within the first after of with the have of hepatic this and hepatic PEPCK gene which is characteristic of the period Hanson R.W. Biochem. J. PubMed Google Scholar). However, PEPCK gene transcription and from the liver can be the period in mice by the of It is that mice are to cAMP and are to the level of glucose in the by either or mice have about of the hepatic and the of to mice the level of increase in the of cAMP as with mice. C. J. M. V. R. and J. E. for mice also have a of the liver and adipose tissue to to and The of glucose by the liver after is than control and the of fatty acid from adipose tissue in the addition of is It likely that the of mice with the immediately after to the level of hepatic cAMP is responsible for the of these animals to glucose at are the responsible for the level of cAMP in the livers of these mice. mice also are to transcription of the gene for PEPCK in the kidney of mice to about of the level noted in control mice. There in the cAMP induction of PEPCK gene that critical for the full response of metabolically important genes to such as and is required for the induction of PEPCK by The there are two noted with the mice is assume that there are factors in the mice with A that to genes critical for the These are as a of the of the which are This is by in which mice for a deletion the gene for C/EBPβ were with from these after One for this is that the for other C/EBP isoforms are in mice with the A the However, there is in the expression of the gene for C/EBPα or in the livers of the the level of expression of the genes for the other members of the C/EBP family has as been in in these mice. C/EBP isoforms bind to three on the PEPCK gene the the P3(I) and the AF2 all three are critical for the transcription of the PEPCK gene in the liver. A deletion in the CRE or the P3(I) site results in of transcriptional induction from the PEPCK gene promoter by both the effects of the (19Liu J. Park E.A. Gurney A.L. Roesler W.J. Hanson R.W. J. Biol. Chem. 1991; 266: 19095-19102Abstract Full Text PDF PubMed Google Scholar). In mice containing a with the PEPCK gene promoter the P3(I) site isoforms of C/EBP are known to bind to this have a level of expression of the in the liver (21Patel Y.M. Yun J.S. Liu J. McGrane M.M. Hanson R.W. J. Biol. Chem. 1994; 269: 5619-5628Abstract Full Text PDF PubMed Google Scholar). A deletion in the AF2 site in the PEPCK gene promoter the effect of on transcription from that promoter when it is into transgenic mice. S. C. and R. The results of gene deletion studies for the of C/EBP isoforms in both the liver-specific expression of the PEPCK gene and the transcription from the PEPCK The by which C/EBP transcription from the PEPCK gene promoter to be There a number of and in now on this critical C/EBP isoforms have been shown to bind to the sequence Mol. Cell. Biol. 1993; PubMed Scopus Google Scholar). 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J. 1995; PubMed Scopus Google Scholar), that of the protein by a kinase can control its transcriptional the there are more than known to bind to and the list is growing N. J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). et al. T. C. M. Genes Dev. 1997; PubMed Scopus Google Scholar) have suggested a model in which is by PKA and binds to in an of with and Because isoforms of C/EBP can also bind to at a it is reasonable to assume that they in the in the transcription of a of genes such as and These genes are at in the the of C/EBP is and the level of is However, there are that PKA of C/EBPα results in of transcription that the of be responsible for induction of PEPCK gene transcription by The CRE of the PEPCK promoter lies immediately adjacent to an domain (12Roesler W.J. Vandenbark G.R. Hanson R.W. J. Biol. Chem. 1989; 264: 9657-9664Abstract Full Text PDF PubMed Google Scholar), and NFI inhibits the induction of transcription from the PEPCK gene promoter by (20Crawford D.R. Leahy P. Hu C.Y. Gronostajski R. Grossman G. Woods J. Hakimi P. Roesler W.J. Hanson R.W. J. Biol. Chem. 1998; 273: 13387-13390Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). However, it has been demonstrated in gene studies that the site of the PEPCK gene promoter is required for the effect of This that there is an interaction between NFI and of which to bind to the PEPCK gene promoter to form a Recently, Leahy et al. R. G. A. R. and R. for evidence that this interaction is with of with NFI the effect of NFI on transcription from the PEPCK gene This effect is for both and that NFI binds to the CREB-binding domain of In of the role of in the regulation of PEPCK gene transcription is that the inhibits transcription from the PEPCK gene promoter Liu J. Hanson R.W. Sen G.C. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Because binding to is as a by which controls it is likely that is also a critical factor in the transcriptional response of PEPCK to Fig. model for the role of C/EBP isoforms in the control of PEPCK gene transcription is from Leahy et al. and the PEPCK gene promoter to the role of in the transcriptional response of and C/EBP, which binds to both the CRE and the P3(I) site of the PEPCK gene with in response to stimulation by The effect of glucocorticoids on PEPCK gene transcription is also the interaction of the glucocorticoid receptor with its binding site on It is also likely that insulin its effect on PEPCK gene transcription by with this The of the AF2 domain in the PEPCK gene promoter results in a of transcriptional induction from the promoter in livers from the glucocorticoid receptor bind to the AF2 region of the PEPCK gene promoter (24Scott D.K. Stromstedt P.-E. Wang J.-C. Granner D.K. Mol. Endocrinol. 1998; 12: 482-491Crossref PubMed Scopus (65) Google Scholar) it its effect on transcription an interaction with of PEPCK gene such as the thyroid hormone receptor or the acid also are known to bind to at N. J. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar) and most likely PEPCK gene transcription that NFI with to PEPCK gene transcription in the liver at a basal level in the of of either C/EBPα or The by which of either or both of these transcription of the PEPCK gene to be for the before