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Insulin Action Gene Regulation

, , and *.

* Corresponding Author: Daryl K. Granner—Department of Molecular Physiology and Biophysics, 707 Light Hall, Vanderbilt University Medical School, Nashville, Tennessee 37232-0615, U.S.A. Email: daryl.granner@mcmail.vanderbilt.edu

Introduction

Insulin regulates metabolism by altering the concentration of critical proteins or by inducing post-translational modifications of preexisting molecules. The latter represents a well-recognized action of insulin, and it has been extensively studied for many years.1-3 By contrast, it is only recently that considerable advances have been made in understanding several aspects of insulin-regulated gene expression.

Although insulin could potentially affect any of the multiple steps in the flow of information from gene to protein, it appears that transcription, mRNA stability and translation represent the primary sites of insulin action. This chapter will principally focus on insulin-regulated gene transcription. It is now clear that insulin can have positive and negative effects on the transcription of specific genes within the same cell.4,5 In addition, the genes regulated by insulin encode proteins involved in a variety of biologic phenomena (Fig. 1). Many, but not all, of these mRNAs direct the synthesis of enzymes that have a well-established metabolic connection to insulin action (Fig. 1). Not unexpectedly, this type of regulation is mostly seen in the primary tissues associated with the metabolic actions of insulin namely liver, muscle and adipose tissue but insulin also regulates gene expression in tissues not commonly associated with metabolic effects.4,5

Figure 1. Insulin regulates the transcription of genes involved in a variety of biologic phenomena.

Figure 1

Insulin regulates the transcription of genes involved in a variety of biologic phenomena. (+): insulin stimulates transcription; (-) insulin inhibits transcription. *Both stimulatory and inhibitory effects have been reported for this gene product.

The cis/trans model of transcriptional control underpins the current understanding of how insulin regulates gene transcription at a molecular level. Briefly stated, the fidelity and frequency of initiation of transcription of eukaryotic genes is mediated by the interaction of cis-acting DNA elements with trans-acting factors. The specific sequence of the cis-acting element determines which trans-acting factor(s) can bind. In addition, the concept of hormone response units, comprising multiple cis-acting elements working in concert, adds a further level of complexity to this basic concept. For example, the combination of cis-acting elements is likely to dictate the precise protein complex that can interact with the gene promoter, and thus the direction, magnitude and regulation of the hormonal response. Importantly, it has become clear that the presence of a cis-acting element within a gene promoter does not always predict the response to a hormone.

Even at the simplest level of the cis/trans model, there are several potential mechanisms by which insulin could influence trancriptional initiation, including regulation of trans-acting factor subcellular localisation, stability and activity (DNA binding and/or transactivation potential). Insulin achieves this regulation by initiating signal transduction pathways that relay the information to the factors, usually resulting in the post-translational modification of the factor (or a regulator) in a manner that alters its function.

Several cis-acting elements that mediate the effect of insulin on gene transcription have been defined. These are referred to as insulin response sequences or elements (IRSs/IREs). To date the general consensus is that there is no consensus IRS/IRE. In this chapter the identification of the best characterized IRSs/IREs and putative trans-acting factors with which they are associated is described in detail. Most of these transcriptional regulators were not initially characterized as insulin regulated factors, but have subsequently been implicated in the regulation of specific gene promoters by insulin.

The physiological importance of insulin-regulated gene transcription is apparent from studies on the glycolytic and gluconeogenic pathways, which can be viewed as a series of three opposing substrate cycles.6 Insulin and glucagon have antagonistic actions on the expression of the genes encoding all of the key regulatory enzymes in these three cycles.6 The biochemical mechanisms that mediate this antagonism are of considerable interest and it is already apparent that different mechanisms are utilized with different genes. Thus, for example, insulin inhibits the stimulation of PEPCK gene transcription by cAMP (see “Phosphoenolpyruvate Carboxykinase (PEPCK)” section), whereas cAMP inhibits the stimulation of hepatic glucokinase gene transcription by insulin.7 Most importantly, although not yet clearly defined, defects in gene expression are likely to play a key role in the pathophysiology of Type 2DM; for example, reduced expression of GLUT2 or glucokinase may be involved in the β cell insulin secretory defect;8,9 increased PEPCK gene expression may lead to an increase in hepatic glucose production (HGP);10,11 whereas reduced GLUT4/HKII expression may be the cause of reduced peripheral glucose utilization (PGU).10,12 In addition, altered TNF-α, resistin, adiponectin, and PTP1B gene expression have been implicated in the generation of insulin resistance.13-17

Insulin Signal Transduction and Gene Expression

Key Signalling Molecules

The Receptor

The insulin receptor (IR) is a heterotetrameric membrane glycoprotein composed of two α subunits and two β subunits linked by disulphide bonds. Binding of insulin to the α subunit leads to a conformational change that promotes autophosphorylation, and activates the intrinsic tyrosine kinase domain of the β subunit. The receptor autophosphorylation on specific tyrosine residues enhances the ability of the IR to recruit and regulate target proteins.18,19

The Receptor Substrates

Proximal substrates of the receptor include members of the insulin receptor substrate family (IRS). There are four closely related IRS's, namely IRS-1, IRS-2, IRS-3 and IRS-4,19-21 as well as the functionally related Shc,22 and p62dok,23,24 that all act as molecular adapters to relay the insulin signal (see ref. 25 for review). IRS-1 and IRS-2 are widely expressed while IRS-4 is expressed in brain, kidney and thymus. Rodents express IRS-3 predominantly within adipose tissue, however this isoform does not appear to exist in human tissue.

The IRS's are phosphorylated on a number of tyrosine residues by insulin receptor tyrosine kinase. Once phosphorylated, the IRS proteins subsequently interact with various effector proteins that contain src homology (SH) 2 domains. These include Grb-2 (growth receptor bound protein-2), the regulatory subunit of PI 3-kinase (p85), the tyrosine kinases fyn and csk and the tyrosine phosphatase SHP2.20,26,27

The Effectors

PI 3-Kinase

Phosphoinositide 3-kinase (PI 3-kinase) is activated by insulin as well as many growth factors and cytokines (for review see refs. 27-30). PI 3-kinase catalyses the phosphorylation of the 3' hydroxyl of phosphatidylinositols. Phosphatidylinositols (PtdIns), PtdIns(4)P and PtdIns(4,5)P2 can all serve as substrates for the PI 3-kinases in vitro. Upon PI 3-kinase stimulation, cellular levels of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 but not PtdIns(3)P, are elevated.27,31,32 Although PtdIns(3,4)P2 can be produced from PtdIns(4)P via the activation of PI 3-kinase, the bulk of this product is generated from the dephosphorylation of PtdIns(3,4,5)P3 by a 5'phosphatase (for review see ref. 33). Thus, PtdIns(3,4,5)P3 is the major phosphatidylinositol that is generated directly upon activation of PI 3-kinase.

A role for PI 3-kinase has been established in almost all of the major actions of insulin such as the regulation of glycogen synthesis, protein synthesis, lipolysis, glucose uptake, membrane trafficking, cytoskeletal arrangement and apoptosis (see reviews refs. 30, 34). Interestingly, the regulation of transcription of genes involved in metabolism by insulin also appears predominantly dependent on PI 3-kinase activation (Table 1 and refs. 35-37).

Table 1. Regulation of gene transcription by insulin.

Table 1

Regulation of gene transcription by insulin.

The products of the PI 3-kinase reaction, PtdIns (3,4,5)P3 and PtdIns (3,4)P2, regulate cellular processes through interactions with proteins that contain pleckstrin homology (PH) domains. The best studied PH domain targets for these lipids are members of the AGC subfamily of protein kinases.38,39 These include PDK1 (3'-phosphoinostide-dependent kinase 1) and PKB (protein kinase B). The activation of other members of this family, such as SGK (serum and glucocorticoid-induced kinase), p70 S6 kinase (S6K), p90rsk and MSK (mitogen and stress activated protein kinase), requires phosphorylation by PDK1,39 therefore they are indirectly regulated by the binding of PtdIns (3,4,5)P3 to PDK1. However, each of these protein kinases also receive signalling inputs from other insulin regulated pathways. For example, S6K activation requires mTOR activity,40 while p90rsk activation requires p42/p44 MAPK activity (see below ref. 41). Thus, inhibitors of mTOR (rapamycin) and the p42/p44 MAPK pathway (e.g., PD98059) block activation of S6K and p90rsk, respectively (Fig. 2). Both of these inhibitors are known to antagonise insulin regulation of a number of genes, implicating these protein kinases in this action of insulin (Table 1).

Figure 2. Insulin signaling pathways potential molecular connections between the insulin receptor at the cell surface and gene expression.

Figure 2

Insulin signaling pathways potential molecular connections between the insulin receptor at the cell surface and gene expression. Commonly used pharmacological inhibitors are given along with their site of action. Arrows indicate activation, I indicates (more...)

The p42/p44 MAPK Cascade

The adaptor molecules Shc and Grb2 bind either singly or in combination to the IRS's through their SH2 or PTB domains.42 Grb2 is complexed to the Ras guanine exchange factor mSOS (son of sevenless). Recruitment of mSOS from the cytosol to the plasma membrane activates Ras (a 21 kDa GTPase). In its active GTP bound form Ras associates with the N-terminal region of the serine/threonine kinase Raf, bringing it to the plasma membrane to become activated.43,44 Activated Raf forms a stable complex with another protein kinase termed MKK1 (mitogen activated protein kinase kinase1, also known as MEK1). Phosphorylation of MKK1 by Raf increases MKK1 activity.45-47 MKK1 in turn, phosphorylates and activates p42/p44 mitogen activated protein kinase (MAPK). p42/44 MAPKs are members of the MAPK superfamily that also include the p38 MAPK and c-jun N-terminal protein kinase (JNK) isoforms.48 These latter MAPKs are activated predominantly by cellular stresses such as osmotic stress, oxidative stress, UV irradiation, heat stress and cytokines.48,49 In some cells insulin is a very weak activator of p38 MAPK and JNK, but the role of these kinases in insulin action is unclear, as strong activation of either of these molecules can promote insulin resistance.50,51

Once activated, p42/p44 MAPK phosphorylates many downstream substrates that are involved in numerous cellular processes such as proliferation, differentiation, cell survival and gene transcription. In addition, MAPK is involved in the activation of several downstream serine/threonine protein kinases, such as the p90rsk isoforms (RSKs 1-3), MSK1/MSK2 (mitogen and stress activated protein kinases) and MNK1/MNK2 (MAPK interacting kinases).52 Once activated, p90rsk phosphorylates downstream targets that are involved in gene transcription, cell cycle regulation and cellular metabolism. The p42/p44 MAPK is key in the mitogenic actions of many hormones and growth factors. Indeed, this molecule appears crucial in the regulation of immediate early genes by insulin in a variety of tissues (Table 1).

Other Insulin Regulated Signalling Molecules

There are multiple protein kinase C isoforms, most (if not all) of which require phosphorylation by PDK1 for activity (see ref. 53 for review). Meanwhile, there is increasing evidence that atypical PKC's (λ/ζ) have an important role in some aspects of insulin action.54-58 In addition, many of the actions of insulin can be mimicked when cells are incubated with phorbol esters (which activate classical and novel although not atypical PKCs).

Insulin treatment of cells can lead to the generation of hydrogen peroxide (H2O2).59-62 Treatment of cells with this agent can mimic many of the effects of insulin.60,63,64 The mechanism of H2O2 generation is not fully understood, nor is the mechanism by which the H2O2 mediates insulin action, however this molecule is one of many that can generate reactive oxygen species which are known to influence the activity of the transcription factor NFκB (for review see ref. 65). Interestingly, recent work has identified the phosphotyrosine phosphatases PTP1B and TCP1α, as targets for H2O2 inhibition (for review see ref. 17). PTP1B, and possibly TCP1α? are key modulators of insulin action, as they dephosphorylate and inhibit the insulin receptor and the IRSs.62,66

The insulin receptor also regulates a complex of proteins including cbl, CAP, caveolin and flotillin, which together represent one branch of the insulin signaling pathways that mobilize GLUT4 transporters (for review see ref. 67). As yet there is little evidence that these signaling molecules are directly involved in the regulation of gene transcription.

Key Insulin/IGF-1-Regulated Transcription Factors

Proto-Oncogenes/Immediate Early Genes

Proto-oncogenes and/or immediate early genes (e.g., jun, fos, elk, fra), were among the first genes shown to be regulated by insulin signaling pathways. Transcription factors such as ELK1, Sap1a, heat shock factor (HSF-1) and serum response factor (SRF) are direct substrates of MAPK. Homodimers of the c-jun family or heterodimers of this family with members of either the c-fos or ATF families, comprise the activator protein-1 (AP1) complex.68 AP-1 was first identified as the mediator of phorbol ester stimulation of the SV40 enhancer.69 These bZIP transcription factors (both jun-jun and jun-fos dimers) bind to the consensus sequence TGA(G/C)TCA known as the TPA response element (TRE). Interestingly, insulin can regulate the AP-1 motif at two levels. First, insulin stimulates transcription of the genes encoding both c-fos and c-jun.70 Second, insulin may mediate an effect on AP-1 through an alteration in the phosphorylation state and transactivation potential of c-fos and c-jun. For example, both p90rsk and MAP kinase can phosphorylate c-fos in vitro71 although it is not known whether this occurs in vivo. Moreover, one report suggests that insulin may augment the phosphorylation and transactivation potential of c-fos via an unidentified kinase, distinct from MAP kinase.72 Although relatively little is known about the regulation of c-fos phosphorylation, the phosphorylation of c-jun by multiple kinases, at multiple sites, has been studied in detail (see ref. 68 for review). MAP kinase, as well as several other insulin-regulated serine kinases, including casein kinase II and GSK-3, phosphorylate c-jun in vitro,73 however, the precise role of these three kinases in insulin regulated gene transcription through AP-1 promoter elements has yet to be established (see refs. 68, 74, 75 for review).

Insulin also regulates both the activity and expression of the c-fos-related antigen-1 (Fra-1).76,77 The regulation of Fra-1 gene expression by insulin is complex but requires the MAP kinase pathway.77 In addition, the MAP kinase pathway, but not the PI 3-kinase pathway, is required for insulin-induced Fra-1 phosphorylation.77

FOXO Family of Transcription Factors

Initial interest in these transcription factors as mediators of insulin action arose when DAF 16 (the Caenorhabditis elegans (C. elegans) homologue of FOXO transcription factors) was found to be genetically linked to molecules related to the mammalian insulin signaling pathway. These are DAF-2 (DAF standing for dauer arrest phenotype), AGE-1, PDK1 and AKT 1 and 2, the mammalian homologues of the insulin/IGF1 receptor, PI 3-kinase, PDK1, and PKB, respectively. Genetic studies in C. elegans indicate that DAF-16 lies downstream of these molecules, and that activation of this pathway leads to the inactivation of DAF-16.78,79 By analogy, insulin is proposed to inhibit FOXO activity, through PI 3-kinase, PDK1 and PKB activation. Subsequently, FKHR, AFX and FKHRL1 (related members of the FOXO family) have been shown to be phosphorylated on three sites by PKB in vitro.80-84 These phosphorylation events are all PI 3-kinase- and PDK1- but not mTOR- or MAPK- dependent.85 FKHR-induced transcription is inhibited by insulin treatment or by the overexpression of a constitutively active Myr-PKB.81,82,86-88 Inhibition is the result of PKB-mediated phosphorylation of FKHR, and subsequent nuclear exclusion (see reviews refs. 89, 90). Interestingly, FKHR or FKHR-L1 can bind to DNA sequences in vitro, that are required for insulin regulation of genes involved in gluconeogenesis (i.e., PEPCK type IRS's, (Table 2).91,92 Thus, it is likely that this family of trans-acting factors plays a key role in this important action of insulin (see “Coordinated Regulation of PEPCK, G6Pase, IGFBP-1 and TAT Gene Expression?” section for a more detailed discussion).

Table 2. Insulin response sequences.

Table 2

Insulin response sequences.

SREBP-1c

Mutagenesis studies on the promoters of the cholesterol biosynthetic genes identified the sterol regulatory element-1 (SRE1; 5'-ATCACCCAC-3') as the promoter sequence required for regulation of expression by cholesterol.93 The Sterol Regulatory Element-Binding Proteins (SREBPs) are a group of proteins that belong to the basic helix-loop-helix leucine zipper (bHLH-Zip) family of transcription factors (for review see refs. 94-96). There are currently three members of the family; namely SREBP-1a, SREBP-1c and SREBP-2. The first two are encoded from the use of alternative first exons of the same gene, while SREBP-2 is expressed from a separate gene.97 The three SREBPs have a common structure (SREBP-1 is approximately 50% identical to SREBP-2), including an N-terminal transcription factor domain of around 480 residues, a middle region of 80 amino acids containing two hydrophobic transmembrane segments, and a C-terminal regulatory domain consisting of 590 amino acids. SREBPs also differ from other bHLH-Zip family members in that they are synthesised as a precursor attached to the endoplasmic reticulum (ER) or the nuclear envelope in a hairpin fashion. The N and C-terminal ends face into the cytoplasm leaving a ‘lumenal loop’ of 31 amino acids projecting into the ER. In order to function as a transcription factor, the N-terminal domain must be cleaved off and this can then move to the nucleus as mature SREBP (for review see ref. 96). This cleavage occurs as a two-step proteolytic cascade. Firstly, SREBP cleavage activating protein (SCAP) binds to the C-terminal half of SREBP and transports it to the Golgi apparatus where the two proteases required for the proteolytic cascade are located. The first proteolytic cleavage (Site 1) is catalysed by the protease S1P (see ref. 98 for review). The second cleavage (catalyzed by S2P) occurs N-terminal of site 1, within the first membrane spanning segment, but only following site 1 cleavage. Insulin may stimulate cleavage and hence the activation of SREBP-1c through regulation of the SCAP inhibitor protein termed Insig-2.99 Insig-2a mRNA is reduced by insulin, as well as by feeding.

SREBP-1 (also known as ADD-1) is responsible for promoting the differentiation of cultured rat adipocytes.100 Interestingly, the SREBPs also bind to the SRE-related sequence CACGTG, better known as an E-box.101 A single amino acid residue is responsible for this dual DNA binding specificity. Thus, whereas most bHLH proteins contain a conserved E-K-X-R sequence, SREBP1 has an atypical tyrosine residue at position 320 (resulting in the sequence E-K-X-Y). Cotransfection experiments with combinations of wild type and Y320R SREBP-1c demonstrate that the homodimeric Y320R mutant binds to the core E-box motif but not to the SRE1. Meanwhile, the heterodimeric Y320R/Y320 and wild-type homodimer bind to both the SRE1 and E-box sequences. Hence it is the presence of the atypical tyrosine at 320 which allows the dual DNA binding specificity.101

The predominant form of SREBP in liver is SREBP-1c,96,102 even though it is a weaker activator of transcription than SREBP-1a (which is constitutively expressed at low levels). However, in cultured cell lines the opposite occurs with SREBP-1a the predominant form.103 During fasting SREBP-1 mRNA and protein levels fall but are restored by refeeding.104 Concomitant increases in the mRNA levels of lipogenic enzymes (such as fatty acid synthase) are observed during refeeding and this is partially blunted in SREBP-1 null mice.105 No changes in SREBP-2 are detected with fasting and refeeding. The response of SREBP-1c to feeding is probably mediated by insulin, since insulin stimulation of rat hepatocytes induces SREBP-1c mRNA and protein, with no change of SREBP-1a or SREBP-2.106 The effect of insulin on hepatic SREBP-1c expression requires PI-3K activity while expression of constitutively active PKB leads to the accumulation of SREBP-1c mRNA.106 Interestingly, the SREBP-1 gene promoter contains an SRE1 site, therefore allowing possible auto-induction. There is also evidence that insulin can directly influence the transcriptional activity of SREBP-1c96,107 and that this may involve the MAPK pathway.107 As well as phosphorylation, SREBP-1 undergoes CBP/p300 mediated acetylation, resulting in its stabilization,108 although it is unclear if this process is regulated by insulin.

One of the best studied SREBP-1 regulated genes is Fatty acid synthetase (FAS). FAS plays a central role in de novo lipogenesis in mammals. Paulauskis and Sul demonstrated that insulin increases FAS gene transcription in the livers of diabetic mice.109 The effect is rapid (3.5-fold after 30 minutes) and reaches a maximum 7-fold increase after 2 hours of insulin treatment.109 cAMP abolishes this stimulation as does cycloheximide, suggesting that on-going protein synthesis is required for this action of insulin. Interestingly, refeeding fasted animals induces FAS promoter activity and promotes SREBP-1c interaction with the FAS promoter.110 Meanwhile, mutation of the SRE1 site (at -150) within this promoter blunts both SREBP-1c binding and the response to refeeding. In addition, mutation of an E-box motif (at -65) blunts both SREBP-1c binding, and induction of the FAS promoter by refeeding.110 Therefore both elements are involved in SREBP1c induction of this gene promoter.

Increased levels of SREBP-1c in transgenic mice reduces the expression of the gluconeogenic (insulin repressed) gene PEPCK,111 while adenoviral-mediated expression of a dominant positive form of SREBP-1c represses PEPCK gene expression in hepatocytes.111,112 However, the PEPCK gene promoter does not contain a consensus SRE1. Therefore the molecular mechanism by which over expressed active SREBP1c represses PEPCK is not clear, but may involve an interaction with the CREB-binding protein.111 Conversely, expression of a dominant negative form of SREBP-1c using adenovirus blocks insulin's ability to induce glucokinase and the lipogenic enzymes, and its ability to repress PEPCK.111

In summary, insulin regulation of SREBP-1c synthesis and/or cleavage and/or transactivating potential, is likely to underlie the regulation of the fatty acid biosynthetic genes, while subtle, if poorly understood, differences in regulation and function of the SREBP isoforms allow different, if overlapping, patterns of gene regulation by insulin and sterols. As such, SREBP-1c is a key mediator of the regulation of gene transcription by insulin.

Sp1

Sp1 belongs to a growing family of transcription factors113,114 that were originally considered basal transcription factors, not involved in hormone-regulated gene expression. However, several genes, including plasminogen activator inhibitor type 1 (PAI-1; 115), and Apo A1116 are now thought to be stimulated by insulin through Sp1 binding elements (see ref. 117 for review). Conversely, there are a multitude of gene promoters that contain Sp1-binding elements but are not insulin regulated. This demonstrates that the context of the Sp1 element in relation to other promoter elements is of utmost importance in gene regulation by insulin.118 Indeed, in some cases Sp1 may actually antagonise or oppose the action of insulin through certain IRS sequences.117

Sp1 has been linked to the regulation of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In their initial studies, Alexander and colleagues demonstrated that insulin causes a 3-fold increase in GAPDH mRNA in the H4IIE rat hepatoma cell line and a 10-fold change in the 3T3 F442A adipocyte cell line.119,120 Using the transient transfection of GAPDH/CAT fusion genes, they then found that the stimulatory effect of insulin on human GAPDH gene expression is mediated through cis-acting sequences located between -488 and +21.120 Further analysis of the effect of insulin on expression of additional GAPDH/CAT fusion gene constructs suggested that the GAPDH promoter contains two independent insulin response elements, designated IRE-A (located between -488 and -409) and IRE-B (located between -308 and -269). The core sequence of IRE-A was observed to have close homology with sequences in the promoters of a number of other insulin regulated genes.121 Now, Wong and colleagues have shown that the GAPDH IRE-A element competes with the Apo A1 gene promoter insulin response sequence for binding of Sp1,116,122 suggesting that Sp1 may also play a role in insulin regulation of GAPDH expression.

The molecular mechanism by which insulin regulates Sp1 is not yet fully elucidated, but is likely to include direct and indirect processes. For example Sp1 binding to the Apo A1 gene promoter (between nucleotides -411 and -404) requires activation of both p42/p44 MAP kinase and protein kinase C.116,123 Meanwhile, insulin may regulate both Sp1 expression124 and DNA binding through a complex interplay with other factors such as AP-1 and Egr-1.125,126

Serum Response Factor and Ternary Complex Factor

c-fos is the cellular homologue of the transforming gene of FBJ murine osteosarcoma virus. Insulin induces c-fos gene transcription in H4IIE cells.127 A number of studies have implicated the involvement of the MAP kinase pathway in insulin-stimulated c-fos gene transcription.128-130 For example, overexpression of wild-type p21ras promotes insulin-stimulated c-fos gene expression128 whereas overexpression of dominant negative mutants of p21ras (and Raf-1) block insulin-stimulated c-fos gene expression.129,130

In experiments using c-fos/CAT fusion genes, the c-fos promoter region from -356 to +109 was sufficient to mediate a response to insulin.131 Mutation of four bases in the c-fos serum response element (SRE), previously shown to abolish the response to serum, also blunted the effect of insulin on this region of the c-fos gene promoter.131 The c-fos SRE (located between -320 and -299 in the c-fos promoter) transfers the insulin response to a heterologous promoter,130 conclusively demonstrating the presence of an IRS/IRE. The sequence of the c-fos SRE is compared with other IRSs in Table 2.

Although a number of SRE binding proteins have been identified,132 the most prominent is the 67 kDa serum response factor (p67SRF). Others include NFIL6, Phox 1 and DBF/MAPF1. An Ets domain binding motif (CAGGAT), recognized by p62TCF (ternary complex factor), is located just 5' of the c-fos SRE. In gel retardation assays, using nuclear extracts from insulin treated cells, the formation of an SRE protein complex (designated “band 2”) increases.133,134 Several lines of evidence indicate that band 2 is a ternary complex consisting of the SRE, p67SRF and p62TCF133,134 and that insulin may stimulate its formation through increased phosphorylation of p62TCF. MAP kinase phosphorylates Elk-1, a protein highly homologous to p62TCF, leading to increased binding135 and/or transcriptional activity of Elk-1.136 Taken together, it is possible that a direct connection between an insulin-stimulated protein kinase and an SRE binding protein has been made, and that this potentially explains the mechanism of insulin action on c-fos gene expression. Unfortunately, detailed mutagenesis of the c-fos SRE by Thompson et al134 demonstrates that the effect of insulin on c-fos gene transcription does not correlate with band 2 formation. However, a second complex (designated “band 3”) has now been identified, the formation of which is also increased in extracts from insulin treated cells.134 The time course for formation of band 3 correlates with the induction of c-fos gene transcription by insulin.134 p67SRF appears to be the only DNA binding protein in the band 3 complex, but Thompson et al suggest that the effect of insulin is mediated indirectly by other unidentified proteins in the band 3 complex that directly associate with p67SRF.134 Thus, although the MAP kinase pathway is implicated in insulin-stimulated c-fos gene transcription, the precise trans-acting factor that mediates this action of insulin (directly or indirectly) remains to be conclusively identified.

Thyroid Transcription Factor-2

Insulin like growth factor-1 (IGF-1) stimulates thyroglobulin gene transcription in rat thyroid cell lines,137 an effect mediated through the -168 to +39 region of the promoter.138 Mutation of any one of three transcription factor binding sites in this region abolishes IGF-1 regulation.138 These three elements bind the thyroid transcription factors (TTF)-1, TTF-2 and a ubiquitous factor (UFA), respectively. IGF-1 induces TTF-2 (but not TTF-1 or UFA) binding, and protein synthesis is required for this effect.138,139 Importantly, this TTF-2 element can confer a stimulatory action of insulin on the expression of a reporter gene when ligated to a heterologous promoter.140

TTF-2 is also required for induction of thyroperoxidase expression by insulin. Again, this action of insulin requires two additional transcription factors, namely TTF-1 and nuclear factor-1 (NF-1).141 Interestingly, NF-1 is also an insulin-induced gene.141

As TTF-2 is expressed specifically in thyroid cells, which lack functional insulin receptors,142 technically this is an IGF-1 response protein. However, it is included in this chapter because the nucleotide sequence of this element has homology with the PEPCK type IRS (Table 2), the IGF-1 and insulin signaling pathways have major overlap, and TTF-2, like FOXO, is a member of the forkhead transcription factor family.143 It is possible that divergent evolution has provided homologous mechanisms for gene regulation in functionally distinct tissues. Therefore the study of the regulation of TTF-2 by IGF-1 may provide clues to the regulation of gene transcription by insulin in more classical insulin sensitive tissues.

Key Insulin-Regulated Gene Promoters

Overview

Insulin is now believed to influence the expression of more than 150 gene products. It is not yet clear how many of these genes are directly regulated at the level of gene transcription but the application of DNA microarray technology is likely to address this in the near future. Obviously it is beyond the scope of this chapter to review the molecular regulation of all of these genes in detail. Therefore, we will focus on the best studied (and possibly best understood) insulin-regulated gene promoters, and present the current understanding of the DNA elements, trans-acting factors and signaling pathways that permit their regulation by insulin. In this way we will provide examples of the complexity of insulin regulation of metabolically important gene promoters, the importance of interactions with other hormones, and develop the concept that insulin may regulate every one of its target gene promoters by different mechanisms.

Phosphoenolpyruvate Carboxykinase (PEPCK)

Phosphoenolpyruvate carboxykinase catalyzes the conversion of oxaloacetate to phosphoenolpyruvate, which is the initial, irreversible step in hepatic and renal gluconeogenesis. The mechanisms that mediate the tissue-specific and hormonally regulated expression of the hepatic cytosolic PEPCK gene have been studied in great detail (for review see refs. 4, 5, 144). The rate of transcription of the PEPCK gene is stimulated by cAMP, retinoic acid, thyroid hormone and glucocorticoids but is inhibited by insulin and glucose. In H4IIE cells the inhibitory effects are dominant, since insulin and glucose prevent cAMP- and glucocorticoid-stimulated PEPCK gene transcription. Insulin primarily inhibits the initiation of PEPCK gene transcription but also reduces the rate of transcript elongation.145

Complex hormone response units, composed of multiple cis-acting elements, are required to manifest the full response to each of these hormones. For example, in the PEPCK gene a glucocorticoid response unit (GRU) mediates the stimulatory action of glucocorticoids.146 Previous studies146-150 showed that this GRU consists of a tandem array (5' to 3') of four accessory factor binding sites (gAF1, from -455 to -431; gAF2 from -420 to -403, gAF3 from -327 to -321; and the cyclic AMP response element [CRE] from -93 to -86) and two glucocorticoid receptor binding sites (GR1 and GR2, from -395 to -349). gAF1, gAF2, gAF3 and the CRE do not function as glucocorticoid response elements themselves. However, when any of these are mutated the glucocorticoid response is reduced by 50-60% and when any combination of two is mutated the promoter is no longer responsive to glucocorticoids; thus GR1 and GR2 are inert by themselves.

Similarly, Hanson and colleagues have shown that four cis-acting elements (designated the CRE, P3[I], P3[II] and P4) are required for cAMP-stimulated PEPCK gene transcription in HepG2 cells.144 More recent evidence implicates gAF3 in the cAMP response as well as the glucocorticoid response in H4IIE cells.151 Together these elements form what can be termed the cAMP response unit (CRU). The CRE, located between -93 and -86 relative to the transcription start site, contains the consensus cAMP response element sequence T(G/T)ACGTCA found in many, but not all, cAMP regulated genes. The other three elements required for the cAMP response in HepG2 cells form a complex unit located between -285 and -238 in relation to the transcription initiation site. Thus, the PEPCK promoter exemplifies an emerging paradigm: complex hormone response units and not simple hormone response elements are prevalent in eukaryotic promoters.152

At least two cis-acting elements mediate the action of insulin on PEPCK gene transcription. One element is located between -437 and -402 (distal) and the other(s) between -271 and +69 (proximal). The distal IRS has been analyzed in detail in the context of a heterologous promoter.88,153,154 The core sequence (located between -413 and -407) is shown in Table 2. This element, that we call the PEPCK-like IRS, may also mediate the negative effect of insulin on the expression of the insulin-like growth factor binding protein-1 (IGFBP-1), G6Pase and tyrosine aminotransferase (TAT) genes (see later). In all of these gene promoters the IRS coincides with an element required for full induction of transcription by glucocorticoids. In the case of PEPCK this is gAF2. Again, in all three genes hepatic nuclear factor-3 (HNF-3 also known as FoxA2) may be the accessory factor required for full induction of gene transcription by glucocorticoids.154-156 However, the available data suggests that HNF-3 does not directly mediate the action of insulin.154 Importantly, in vivo footprinting studies reveal no change in the footprint over the PEPCK IRS following treatment of H4IIE cells with insulin.157

The phosphatase inhibitor, okadaic acid, mimics the action of insulin on PEPCK gene transcription158 suggesting that, as with most of insulin's actions, changes in protein phosphorylation are involved in these effects. Indeed, regulation of PEPCK gene transcription by insulin requires PI 3-kinase activity, but not mTOR or MAP kinase activity (Table 1 and refs. 35-37). In addition, strong activation of PKB/Akt159 or pharmacological inhibition of the PKB-inhibited kinase glycogen synthase kinase-3 (GSK3),160 represses PEPCK transcription. This suggests the presence of a linear signaling pathway from PI 3-kinase, through PKB and GSK3, to a PEPCK IRS-binding protein. In addition, there is data linking the FOXO transcription factor family with insulin regulation of this gene promoter (see “Coordinated Regulation of PEPCK, G6Pase, IGFBP-1 and TAT Gene Expression?” section).

Interestingly, many other cellular manipulations affect the expression of PEPCK. Repressing manipulations include; overexpression of active SREBP-1c,111 active Ras, active Raf,37 or LIP;161 oxidative stress,64 activation of AMP-activated protein kinase;162 or treatment of cells with phorbol esters,163 or EGCG, a constituent of green tea.164 Thus, much more information will be required before the complicated molecular processes involved in the regulation of PEPCK gene transcription are fully appreciated.

Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1)

The insulin-like growth factor binding proteins are a family of six secreted proteins, designated IGFBP-1 to 6, that specifically bind IGF-I and IGF-II but do not bind insulin. The structure of the IGFBP proteins and the differential, tissue-specific and hormonal regulation of expression of the IGFBP genes has been reviewed elsewhere.165

The multihormonal regulation of the PEPCK and IGFBP-1 genes is similar in that cAMP, thyroid hormone and glucocorticoids stimulate the hepatic expression of both genes whereas insulin has a dominant inhibitory effect (see ref. 166 for review). The structural organization of the PEPCK and IGFBP-1 promoters also has similarities. Two glucocorticoid response elements (GRE) and an IRS are present in the IGFBP-1 gene promoter.167-169 In the human promoter the IRS is located between (-120 and -96) and the two GREs are found between (-110 and -84) and (-198 and -173).167,170 Powell and colleagues defined the human IGFBP-1 IRS by analyzing the ability of insulin to repress basal IGFBP-1 reporter gene expression.167 A deletion that abolished the negative effect of insulin was identified. The region encompassed by the deletion was then shown to confer an inhibitory effect of insulin on CAT reporter gene expression directed by a heterologous promoter.167 The core IRS sequence, T(G/A)TTTTG, is the same as that found in the distal IRS of the PEPCK gene (Table 2), but the PEPCK gene promoter has a single copy of this element whereas the IGFBP-1 gene promoter has two copies arranged as an inverted palindrome.

In a remarkably similar fashion to the distal PEPCK IRS, the IGFBP-1 IRS also acts as an accessory factor binding site that is required for the glucocorticoid response. Thus, mutation of the IGFBP-1 gene IRS abolishes the induction of human IGFBP-1 gene transcription by glucocorticoids even though both GREs are intact.154,170 As described in the preceding section, the accessory factor is thought to be HNF-3.154,156

However, although this similarity in promoter structure exists, many differences in the signaling pathways involved in the regulation of PEPCK and IGFBP1 expression have recently been identified (see “Coordinated Regulation of PEPCK, G6Pase, IGFBP-1 and TAT Gene Expression?” section for details). Therefore, it appears that the presence of an inverted palindrome of the IRS, as opposed to the single sequence in the distal IRS of the PEPCK promoter, results in a distinct molecular link between the insulin receptor and the promoter element.

Glucose 6-Phosphatase Catalytic Subunit (G6Pase)

Glucose 6-phosphatase converts G6P to glucose, the final step in both gluconeogenesis and glycogenolysis. This enzyme activity is expressed mainly in liver and kidney, and is catalyzed by a multi-component integral membrane system within the endoplasmic reticulum.171-174 Current thinking suggests that the complete system requires a catalytic subunit (G6Pase), along with specific transporters for glucose, G6P, and inorganic phosphate.171-174 Inactivating mutations in the G6Pase gene result in reduced hepatic glucose production and are responsible for glycogen storage disease type 1a.175 In contrast, over expression of G6Pase in liver cells results in increased hepatic glucose production.176-178

Insulin acutely inhibits G6Pase enzyme activity, at least partly, and this may be PI 3-kinase-dependent,179 but the major form of inhibition of this activity occurs at the level of gene transcription.180,181 The overall hormonal regulation of G6Pase gene expression is similar to that for PEPCK and IGFBP-1. Glucocorticoids and cAMP stimulate gene transcription, while insulin represses both basal and induced gene expression.180,182 However, in contrast to PEPCK, glucose induces G6Pase gene transcription, but this is also antagonised by insulin.183

Two regions of the mouse G6Pase gene promoter, designated A (from -231 to -199) and B (from -198 to -159), are required for complete repression of basal G6Pase gene transcription by insulin.180,182 These regions are highly conserved between species, including human.92 Region A acts as an accessory element that enhances the action of insulin on region B.182 Therefore Region B is referred to as the G6Pase IRS, however, the two regions together comprise the G6Pase insulin response unit (IRU). HNF-1 is the accessory factor that binds to Region A,182 while Region B actually contains three PEPCK-like IRS motifs that are arranged in tandem and designated IRS-1 to IRS-3 (or PEPCK-type B, A and C, respectively, (see Table 2). 180,184 IRS-2 has an identical sequence to the PEPCK IRS, however IRS-1 (TGTTTTT) and IRS-3 (TATTTTA), differ by one and two nucleotides, respectively. Interestingly, these differences in sequence alter the protein binding characteristics of each IRS,184 suggesting that the molecular mechanism of insulin regulation of G6Pase differs from that for the PEPCK IRS (see “Coordinated Regulation of PEPCK, G6Pase, IGFBP-1 and TAT Gene Expression?” section). Similarly, while the PEPCK IRS also functions as a key binding site for an accessory factor for glucocorticoid induction, the G6Pase IRS motifs may be directly colocalized with a glucocorticoid receptor binding site (O'Brien unpublished observations).

Tyrosine Aminotransferase (TAT)

The tyrosine aminotransferase gene has served as a paradigm for the hormonal regulation and tissue-specific expression of hepatic genes.185 Schutz and colleagues defined three far-upstream enhancers that mediate this regulation.186 An enhancer at -11 kbp mediates liver specific TAT gene expression, whereas enhancers at -3.6 kbp and -2.5 kbp mediate the induction of TAT gene transcription by cAMP and glucocorticoids, respectively. Grange and colleagues have characterized an additional glucocorticoid-dependent enhancer at -5.4 kbp.187 As described above for the PEPCK gene, all three hormone-dependent enhancers in the TAT gene promoter are actually hormone response units in that multiple accessory factor binding sites are required to manifest the full response to cAMP and glucocorticoids.185,187

Regulation of TAT gene expression by insulin has been studied in considerable detail, with several different results, depending on the cell line studied (see ref. 188 for review). Meanwhile, Ganss et al185 proposed that insulin mediates its negative effect on cAMP- and glucocorticoid-stimulated TAT gene transcription through the -3.6 kbp and -2.5 kbp enhancers, respectively. They suggest that insulin acts to disable the TAT CRE in the -3.6 kbp enhancer but this action of insulin may be mediated indirectly through the well-characterized ability of the hormone to stimulate cAMP phosphodiesterase activity.189

Schütz and colleagues have shown that a CCAAT box, CACCC box and an HNF-3 binding site found in the vicinity of the -2.5 kbp TAT GRE are all required for full glucocorticoid-stimulated TAT gene transcription.186 The HNF-3 binding site, not the CCAAT box or CACCC box, is the site of insulin action in the -2.5 kbp enhancer.185 This HNF-3 binding site contains a TGTTTGT motif similar to the PEPCK/IGFBP-1 core IRS. Although the detailed mutagenesis analyses required to prove that this sequence within the TAT HNF-3 motif is the site of insulin action have not been reported, it is possible that insulin mediates its negative effect on PEPCK, IGFBP-1, G6Pase and TAT gene transcription through the same trans-acting factor.

Coordinated Regulation of PEPCK, G6Pase, IGFBP-1 and TAT Gene Expression?

As discussed above, it is clear that structurally related DNA sequences are important in insulin inhibition (as well as glucocorticoid induction) of PEPCK, G6Pase, and IGFBP-1 (Table 2). Meanwhile, the FOXO proteins FKHR, FKHR-L1 and AFX are a family of trans-acting factors whose activity is repressed by insulin (see “FOXO Family of Transcription Factors” section). Taken together with the finding that the FOXO proteins can bind to the G6Pase, PEPCK, TAT and IGFBP-1 IRS's in vitro,91,92 a strong case can be made that these factors play an important role in inhibition of one or more of these gene promoters by insulin. In agreement with this possibility, PI 3-kinase activity is required for insulin inhibition of the FOXO proteins,85 as well as G6Pase, PEPCK and IGFBP-1 gene expression.35,160,162,181,190 However, other studies have brought this simple hypothesis into question, or at least suggest that distinct mechanisms are likely to be involved in the regulation of each of these gene promoters by insulin.

For example, Hall et al placed the IGFBP-1 IRS upstream of a thymidine kinase promoter and mutated single nucleotides in each half of the inverted palindromic sequence.88 The ability of FKHR-L1 to activate these mutant IRS's, and the effect of insulin on these promoters, with or without FKHR-L1 overexpression was assessed. A clear dissociation was observed between FKHR-L1 binding in vitro and the ability of insulin to repress fusion gene expression in cells.88 However, a perfect correlation was observed when FKHR-L1 was over expressed. This suggests that the endogenous insulin response factor that binds to the IGFBP-1 IRS is not FKHR-L1. In contrast, fasting IGFBP-1 gene expression is elevated in transgenic mice over expressing constitutively active FKHR.191 Also, heterozygous deletion of FKHR suppresses the elevation of IGFBP-1 gene expression that occurs in fasting mice with a simultaneous heterozygous deletion of the insulin receptor gene.191 Surprisingly, reduced expression of FKHR alone in mice has no effect on IGFBP-1 gene expression.191 Nevertheless, this genetic data would support a role for FKHR in the regulation of the IGFBP-1 gene.

Detailed studies on the signaling mechanisms used by insulin to regulate IGFBP-1 gene expression suggest that there must be other trans-acting factors involved in this action of insulin. For example, the mTOR inhibitor rapamycin blocks the regulation of IGFBP-1 expression by insulin,192,193 demonstrating a requirement for mTOR in the pathway from insulin to the IGFBP-1 promoter (insulin regulation of FOXO activity is unaffected by rapamycin). In addition, insulin requires PI 3-kinase activity, but not MAP kinase or mTOR activity, in order to reduce PEPCK35 and G6Pase gene expression.181 Therefore, this rapamycin sensitive pathway is not common to all three of these insulin regulated genes. Similarly, although phorbol ester, okadaic acid and H2O2 treatment of hepatoma cells mimic insulin and repress PEPCK and G6Pase gene transcription, these agents antagonize insulin repression of IGFBP1 gene transcription.158,163,190,194 The effect of such cellular manipulations on FKHR activity is not yet fully characterized. However, there is clearly distinct molecular wiring between the insulin receptor and the IGFBP-1 gene promoter compared to the pathway between the insulin receptor and the G6Pase or PEPCK gene promoters.

Similarly, the molecular regulation of the PEPCK and G6Pase gene promoters by insulin is likely to have distinct components. For example, stable expression of FKHR in hepatoma cells induces G6Pase expression, without affecting PEPCK gene expression.195 Meanwhile, expression of constitutively active FKHR in mice also induces G6Pase expression levels without much effect on PEPCK expression.191 This implicates FKHR in the regulation of G6Pase but not PEPCK gene expression. However, heterozygous deletion of FKHR blunts the increase in both G6Pase and PEPCK gene expression that is associated with haploinsufficiency of the insulin receptor.191 Whether this reflects an overall effect of loss of FKHR on insulin sensitivity, or a direct function of FKHR in the regulation of these genes is not yet clear.

Therefore, it is quite likely that although it makes metabolic sense to coordinate the molecular regulation of these gene products, distinct signaling mechanisms and different DNA binding protein complexes have evolved to permit appropriate regulation by insulin.

Conclusions

Now that multiple IRSs/IREs have been characterized, it is apparent that a unique consensus sequence does not exist (Table 2). Several genes whose transcription is inhibited by insulin, namely PEPCK, G6Pase, IGFBP-1 and TAT, appear to share a related core IRS. However, much remains to be learned concerning the trans-acting factors that bind to the identified IRSs/IREs, and about the precise mechanism(s) of insulin signaling to these proteins. Interestingly, it appears that even related IRS/IRE sequences are regulated by different insulin signaling pathways, potentially regulating the binding of distinct trans-acting factors to the transcriptional initiation complex. The development of DNA microarray technology combined with genetic manipulation of cells, tissues and animals, is leading to an explosion of studies intended to categorize all insulin-regulated gene promoters through their dependence on insulin signaling molecules and specific trans-acting factors. Hopefully this will aid in the clarification of the dependency and sufficiency of each IRS/IRE sequence and the importance of interactions with associated gene promoter elements.

In summary, much remains to be learned, but the importance of these studies is emphasized by the fact that many of the mutations that result in Maturity Onset Diabetes of the Young occur in transcription factors,196,197 and that the altered rate of transcription of genes associated with insulin resistance almost certainly contributes to the serious complications of, if not the development of, type 2 diabetes mellitus, dyslipidemia and hypertriglyceridemia.

Acknowledgements

Due to the limitation of the number of references we apologize to those authors whose work has not been cited. We appreciate the many helpful discussions we have had with members of our laboratories, and with other colleagues. In particular we thank Christopher Lipina for his input, and Deborah Brown, who was a great help in the preparation of this chapter. C.D.S is the recipient of the Diabetes UK Senior Fellowship (RD02/002473). The work discussed was supported by DK35107 and DK07061 (to D.K.G), DK56374 and DK61645 (to R.O'B), and also the Vanderbilt Diabetes Research and Training Center (DK20593).

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