REVIEW ARTICLE Control of mammalian gene expression by amino acids, especially glutamine Carole Brasse-Lagnel, Alain Lavoinne and Annie Husson ´ Appareil Digestif, Environnement et Nutrition, EA 4311, Universite de Rouen, France Keywords AARE; amino acids; ATF; gene transcription; glutamine; mammalian cells; NF-jB; NSRE; signalling pathways; transcription factors Correspondence ´ A Lavoinne, Groupe ADEN, Faculte de ´ Medecine-Pharmacie de Rouen, 22 Boulevard Gambetta, Rouen Cedex, France Fax: +33 35 14 82 26 Tel: +33 35 14 82 40 E-mail: Alain.lavoinne@chu-rouen.fr (Received 12 November 2008, revised January 2009, accepted 21 January 2009) doi:10.1111/j.1742-4658.2009.06920.x Molecular data rapidly accumulating on the regulation of gene expression by amino acids in mammalian cells highlight the large variety of mechanisms that are involved Transcription factors, such as the basic-leucine zipper factors, activating transcription factors and CCAAT/enhancer-binding protein, as well as specific regulatory sequences, such as amino acid response element and nutrient-sensing response element, have been shown to mediate the inhibitory effect of some amino acids Moreover, amino acids exert a wide range of effects via the activation of different signalling pathways and various transcription factors, and a number of cis elements distinct from amino acid response element/nutrient-sensing response element sequences were shown to respond to changes in amino acid concentration Particular attention has been paid to the effects of glutamine, the most abundant amino acid, which at appropriate concentrations enhances a great number of cell functions via the activation of various transcription factors The glutamine-responsive genes and the transcription factors involved correspond tightly to the specific effects of the amino acid in the inflammatory response, cell proliferation, differentiation and survival, and metabolic functions Indeed, in addition to the major role played by nuclear factor-jB in the anti-inflammatory action of glutamine, the stimulatory role of activating protein-1 and the inhibitory role of C/EBP homology binding protein in growth-promotion, and the role of c-myc in cell survival, many other transcription factors are also involved in the action of glutamine to regulate apoptosis and intermediary metabolism in different cell types and tissues The signalling pathways leading to the activation of transcription factors suggest that several kinases are involved, particularly mitogen-activated protein kinases In most cases, however, the precise pathways from the entrance of the amino acid into the cell to the activation of gene transcription remain elusive A growing number of reports clearly demonstrate that amino acids are able to control physiological functions at different levels, including the initiation of protein translation, mRNA stabilization and gene transcription [1–3] Although the molecular mechanisms involved in the control of gene expression by amino Abbreviations AAR, amino acid response; AARE, amino acid response elements; ADSS1, adenylosuccinate synthetase; AP, activating protein; ASCT2, Na+dependent transport system; ASNS, asparagine synthetase; ASS, argininosuccinate synthetase; ATF, activating transcription factor; C/EBP, CCAAT/enhancer-binding protein; CHOP, C/EBP homology binding protein; ERK, extracellular signal-related kinase; FXR, farnesoid X receptor; HIF, hypoxia-inducible factor; HNF, hepatocyte nuclear factor; HSF, heat shock factor; IL, interleukin; IjB, inhibitor of kappa B; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; NF-jB, nuclear factor kappa B; NSRE, nutrient-sensing response elements; PPAR, peroxysome proliferator-activated receptor; RXR, retinoid X receptor; TNF, tumour necrosis factor 1826 FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works C Brasse-Lagnel et al Glutamine and transcription factors acid availability have been extensively studied in lower eukaryotes such as yeasts [4], the control of transcriptional events including signalling pathways, transcription factors and their corresponding cis-acting DNA sequences is still unclear in mammalian cells Nevertheless, some in vitro experiments have shown that under specific conditions such as amino acid deprivation, the expression of individual genes is changed via the activation of specific transcription factors and regulatory sequences The first studies, performed about 20 years ago, concerned stimulation of ASS gene transcription by arginine deprivation in human cell lines [5] A small region (149 bp) of the ASS gene promoter was proposed to be involved in arginine sensitivity, suggesting the existence of an arginine responsive element, but the specific cis element within this region and the involved transcription factor(s) were not identified [6,7] Further extensive studies on the ASNS [8,9] and CHOP genes [10,11] allowed characterization of specific responsive sequences in their promoter, which were named either nutrient-sensing response elements (NSRE) or amino acid responsive elements (AARE) Specific transcription factors involved in the amino acid response pathway (AAR) were also identified, and are members of the basic region/leucine zipper superfamily of transcription factors [12,13] In parallel, some amino acids involved in many cellular functions, particularly glutamine, were shown to exert a wide range of effects via the activation of different signalling pathways and transcription factors In this case, a number of cis elements distinct from AARE/ NSRE were shown to respond to changes in amino acid concentration Although the molecular details of these effects are not completely known, the heterogeneity of the involved factors might suggest multiple AAR pathways depending on the amino acid studied, the cell type used and the gene promoter configuration Moreover, this complexity is enhanced by the fact that some target genes encode transcription factors which may in turn act on many subordinated genes [14] Among the amino acids, glutamine has the ability to regulate gene expression in a number of physiological processes, as reported in a recent review illustrating the vast panel of regulated genes [15] Thus, in this review, we intend to summarize recent data obtained on the molecular mechanisms involved in the effects of amino acids on gene expression, focusing on the transcription factors responsive to glutamine The importance of AARE sequences and ATF/C/EBP transcription factors in the AAR pathway Tables and summarize the molecular data obtained on the transcriptional effects of different amino acids (except glutamine), together with the identified transcription factors and the responsive elements involved Most of the data concern the inhibitory effect of amino acids Initial studies were performed to explore the molecular mechanisms involved in the inhibitory effect of asparagine and histidine on the expression of ASNS and that of leucine on CHOP (also known as GADD 153) gene expression (Table 1) Indeed, the first identification of a sequence responsive to amino acid (AARE) was performed by Guerrini et al [8], while studying the functionality of the ASNS gene promoter in asparagine- or leucine-deprived ts11 and HeLa cells Further studies by Kilberg’s group on the inhibiting effect of histidine on the human ASNS gene in HepG2 Table AARE-NSRE sequences and the inhibiting effect of amino acids on gene transcription Cell model Amino acid(s) deprivation Target genea Transcription factor(s) involved Localization of the responsive sequence(s) Responsive sequence(s)b HeLa HepG2 HeLa NIH/T3T Asparagine Histidine Leucine Cystine ASNS ASNS CHOP xCT (ns) C/EBPb, ATF4 ATF2, ATF4 ATF4 Histidine Histidine C/EBPb SNAT2 HepG2 Rat C6 glioma Histidine All amino acids ATF3 CAT-1 ATF4 ATF4, C/EBPa, b, d ATF3, ATF4, C/EBPb ATF4, C/EBPb, ATF3 AARE 5¢-CATGATG-3¢ NSRE 5¢-TGATGAAAC-3¢ AARE 5¢-ATTGCATCA-3¢ AARE 5¢-TGATGCAAA-3¢ and 5¢-TTTGCATCA-3¢ multiple sites AARE 5¢-TGATGCAAT-3¢ [8] [13,16,18] [12,21] [30] HepG2 HepG2 5¢-Flanking region (-70/-64) 5¢-Flanking region (-68/-60) 5¢-Flanking region (-310/-302) 5¢-Flanking region (-94/-86 and -76/-68) 3¢-UTR region (+1554/+1646) First intron (+712/+724) 5¢-Flanking region (-23/-15) First exon (+45/+53) 5¢-TGATGCAAC-3¢ AARE 5¢-TGATGAAAC-3¢ [33] [28,29] a Transcription factors studied as regulated target genes are given in bold b Reference [34] [31,32] Accessory sites are not specified FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works 1827 Glutamine and transcription factors C Brasse-Lagnel et al Table Other proposed sequences involved in the effect of amino acids on gene transcription Cell model Rat liver in vivo Human endothelial HepG2 HUVEC Mouse macrophages Mouse cerebellum a Amino acid(s) manipulation Protein-free diet Homocysteine addition Phenylalanine deprivation Homocysteine addition Homocysteine addition Glutamate addition Transcription factor involved Localization of the responsive sequence Proposed responsive sequencea IGFBP-1 stimulation Endothelin-1 inhibition Albumin inhibition USF1-USF2 activation AP-1 inhibition E box : -88/-83 (5¢-CACGGG-3¢) AP-1 site (5¢-GTGACTAA-3¢) HNF-1 site ATF3 stimulation Gcl stimulation ATF2 and c-jun activation Nrf2 activation Glast inhibition c-jun activation 5¢-Flanking region (AARU: -112/-77) 5¢-Flanking region (-109/-102) 5¢-Flanking region (-60/-46) 5¢-Flanking region (-92/-84) 5¢-Flanking region (-6.5 kb/-3.8 kb) 5¢-Flanking region (-135/-129) Target gene HNF1a inhibition Reference [36] [37] [38] ATF/CRE sequence 5¢-TTACGTCA-3¢ ARE sequence [39] AP-1 site [43] [40] Accessory sites and additional factors are not cited cells specified that this element also responds to glucose addition It was subsequently referred to as NSRE-1, a composite site which could be recognized in vitro by two factors, namely the CCAAT/enhancerbinding protein-b (C/EBP-b) and activating transcription factor-4 (ATF4) [13,16] An additional sequence, named NSRE-2, located 11 nucleotides downstream of NSRE-1, was found to amplify NSRE-1 activity in response to amino acid starvation Accessory sequences such as GC boxes were also required for maximal activation of the ASNS gene [9,17,18] In addition to the involvement of ATF4 and C/EBP-b, an additional regulatory role of ATF3 on transcription of the ASNS gene was also recognized following histidine deprivation in HepG2 cells [19] Further studies demonstrated that stimulation of ASNS gene transcription following ATF4 binding to NSRE-1 might involve acetylation of histones H3 and H4, and the subsequent binding of general transcription factors [20] In parallel, extensive studies from Fafournoux’s group demonstrated that transcription of the human CHOP gene is stimulated by leucine deprivation in HeLa cells via a specific AARE in the promoter This element was able to bind ATF2 and ATF4 in vitro [12,21] Furthermore, it was shown that binding of ATF4 and phosphorylation of ATF2 bound to CHOP AARE were essential for the acetylation of histones H4 and H2B within the AARE sequence leading to the response to leucine starvation [22] This result was recently supported by the observation that the p300/CBP-associated factor, a transcriptional co-activator with intrinsic histone acetyltransferase activity, could interact with ATF4 to enhance CHOP transcription following leucine deprivation [23] Although the CHOP AARE and ASNS 1828 NSRE-1 sequences shared structural and functional similarities, the CHOP AARE sequence is able to function alone and is more sensitive to amino acid deprivation than NSRE-1 alone [24] These data show that ATF factors might largely contribute to promote the changes in the chromatin structure required to enhance transcription of amino acid-regulated genes The mechanism(s) of detection of amino acid limitation by the ARR pathway relies on free tRNA accumulation which activates a stress kinase called the GCN2 kinase This kinase, in turn, phosphorylates the eIF2a, thereby inhibiting general protein synthesis [25,26], as shown previously in yeasts Paradoxically, in this condition, the specific synthesis of some transcription factors from pre-existing mRNAs such as ATF4 was observed with the subsequent activation of target genes, namely those containing an AARE Signalling pathways involved in these effects were recently studied in human hepatoma cells revealing the activation of specific mitogen-activated protein kinase cascades, such as the mitogen-activated protein kinase kinase/extracellular signal-related kinase (ERK) pathway [27] Table also shows that, in addition to original AARE and NSRE, similar functional sequences were identified in various regions of other amino acid-regulated genes involved in amino acid transport such the CAT-1 gene [28,29], the xCT gene encoding a component of the cystine/glutamate transport system (system xÀ ), [30] and the SNAT2 gene encoding an isoform of c the system A amino acid transporter [31,32] Similarly, such sequences were also found in genes encoding transcription factors, such as ATF3 [33] and C/EBP-b [34] Again, evidence was obtained for increased FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works C Brasse-Lagnel et al Glutamine and transcription factors binding of ATF4 and C/EBP-b to these sequences following amino acid deprivation, emphasizing the major role played by ATF and C/EBP factors in the inhibiting effect of amino acids on gene expression Concerning the stimulation of gene expression by the presence of amino acids, only one gene, Pept 1, encoding a peptide transporter, was shown to contain an AARE-like sequence activated by phenylalanine addition but the functionality of the sequence in the promoter has not been further specified [35] Transcription factors other than ATF/C/EBP are involved in the effects of amino acids In addition to ATF/C/EBP factors and specific AARE sequences, a few other transcription factors and their corresponding cis elements are modulated by amino acids (Table 2) Thus, increased DNA-binding activity of the upstream stimulatory factors USF1 and USF2 on the E box of the IGFBP-1 gene promoter was observed in the liver of rats fed a protein-free diet [36] Similarly, decreased binding of the activating protein (AP-1) on the promoter of the endothelin-1 gene was observed following homocysteine addition in endothelial cells, resulting in inhibition of endothelin-1 expression [37] In these two cases, the presence of amino acid(s) resulted in inhibition of the DNA binding of the involved transcription factors By contrast, the presence of amino acid may also result in stimulation of the DNA binding of the involved transcription factor Thus, in phenylalanine-deprived hepatoma cells, the transcriptional activity of the hepatocyte nuclear factor-1 (HNF-1) decreased, limiting expression of the albumin gene [38] Another example is brought about by the activation of ATF2 and c-jun in homocysteinetreated endothelial cells, stimulating ATF3 gene transcription [39] This was also observed in homocysteine-treated macrophages in which activation of nuclear factor-E2-related factor (Nrf2) stimulated the gcl gene via an antioxidant response element, a pathway involving the MEK/ERK1/2 kinases [40] Figure summarizes the different genes regulated by amino acids with the identified transcription factors and responsive sequences It is beyond the scope of this review to detail the case of glutamate, a major excitatory neurotransmitter, regulating the transcription of numerous genes in the central nervous system [41,42] Indeed, glutamate acts through its binding to specific membrane receptors, which is not the case for the other amino acids In this context, glutamate-responsive elements were recently identified as a functional AP-1 site in the 5¢-flanking sequence of some genes in mammalian neurons and glial cells, such as the glast gene in mouse cerebellum [43] However, it should be pointed out that glutamate may also exert Amino acids Deprivation Deprivation or addition Cultured cells Cytoplasm ? AAR pathway Cultured cells or in vivo study Nucleus C/EBPs, ATFs NSRE or AARE Fig Schematic representation of the influence of amino acids on gene expression in mammals The figure is limited to the transcription factors involving AARE and NSRE, as well as the other known transcription factors where responsive sequences were identified in the gene Details of the responsive sequences are given in Tables and Target genes USFs, AP-1, HNF-1, ATF2, Nrf2 Corresponding sequences ASNS,CHOP, xCT,C/EBP, SNAT2,ATF3, CAT-1 Target genes IGFBP-1,Endothelin-1, Albumin,ATF3,Glast, Gcl Specific mRNAs FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works 1829 Glutamine and transcription factors C Brasse-Lagnel et al transcriptional regulation via its production from the intracellular metabolism of glutamine, as we [44] and others [45] have recently reported in intestinal cells Finally, Table summarizes studies reporting the influence of amino acid removal or addition on some transcription factors, either at the level of their activation (mainly by their ability to bind DNA) or at the level of their expression (mRNA or protein) In the latter case, the specific responsive sequences in the target genes were not characterized further It can be noted Table Transcription factors involved in the action of amino acids on gene expression Amino acid(s) manipulations Factor(s) implied Inhibiting effect resulting from the presence of amino acids Pooled amino acids deprivation Increased c-myc mRNA stabilisation Dietary protein restriction Increased HNF-3, HNF-1, C/EBP, Sp1 binding and HNF-1 mRNA level Leu + Ile + Cys + Trp Increased CHOP mRNA and protein levels deprivation Protein-free diet Increased HNF-3c mRNA level Increased Id2 mRNA level Increased FoxO4 mRNA level Methionine Deprivation Increased c-jun, c-myc and jun-B mRNA levels Addition Decreased p53 mRNA and protein levels Homocysteine addition Decreased NF-jB binding Decreased AP-1 binding Decreased PPAR a, c mRNA and protein levels Leucine deprivation Increased NF-jB binding Histidine Deprivation Increased ATF3 mRNA stabilisation Addition Inhibited NF-jB activation Arginine Deprivation Increased NF-jB binding Addition Inhibited PPAR-c binding Leu or Ile or Val Addition Inhibited SREBP-2 mRNA level Cysteine Deprivation Increased ATF3, C/EBPb, C/EBPc, FoxO3A and Gadd45 mRNA levels Stimulating effect resulting from the presence of amino acids Dietary protein restriction Inhibited HNF-4 and NF1 binding Mixed amino acids addition Increased phosphorylated STAT3 Tryptophan addition Increased AP-1 binding Homocysteine addition Increased CHOP, Gadd45, ATF4, Id-1, SREBP and YY1 mRNA levels Increased c-Fos mRNA level Increased ATF4 protein level Increased ATF4 mRNA level Increased NF-jB binding Arginine addition Glycine addition 1830 Activated IjB kinases and increased NF-jB binding Increased CREB binding Increased AP-1 binding Increased AP-1(c-jun) binding Increased NF-jB protein Increased PPAR-c mRNA level Experimental model Reference Cultured rat hepatocytes Rat liver in vivo [46] [14] Mouse fibroblasts [48] Rat liver in vivo [49] [50] [51] CHO cells Human breast cancer cells TNF-stimulated HUVEC NIH/3T3 cells Human monocytes Mouse embryo fibroblasts [52] [53] [54,55] [56] [57] [58] HepG2 cells TNF-induced Caco-2 cells [47] [59] Murine keratinocytes Post-ischaemic rat jejunum [60] [61] Human intestinal cell line [62] Human hepatoma cells [63] Rat liver in vivo Perfused rat heart Human fibroblasts HUVEC [14] [64] [65] [66] Murine macrophages Human retinal cell line HUVEC Rat aortic muscle cells Human VSMCs Rat VSMCs HUVEC Rat kidney mesangial cells Human endothelial cells [67] [68] [69] [70] [71] [72] [73] [74] [75] HepG2 cells Rat hepatocytes Rat jejunum in vivo Diabetic rat pancreas Mouse adipocytes [76] [77] [78] [79] [80] FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works C Brasse-Lagnel et al Glutamine and transcription factors that the stabilization of specific mRNAs encoding transcription factors can contribute to the stimulation of gene expression following amino acid deprivation, as demonstrated for c-myc and ATF3 [46,47] The observations reported in Table underline the diversity of the mechanisms by which amino acids modulates gene expression It can be seen that some amino acids act by inhibiting several transcription factors [14,46–63], whereas others act through a stimulatory effect [14,64–80] Interestingly, two amino acids, namely homocysteine [54,70–74] and arginine [60,79], are able to inhibit or stimulate nuclear factor kappa B (NF-jB), depending on the physiological conditions and cell types studied This underlines the need to understand the molecular mechanism by which these amino acids act Because increased circulating concentrations of homocysteine have been reported to be associated with a variety of diseases [81], the molecular mechanisms involved in the effects of the amino acid were extensively studied, revealing multiple regulated transcription factors (Tables and 3) Thus, as assessed by these studies, the regulation of transcription by amino acids relies on different mechanisms involving various transcription factors, but their corresponding cis elements are not yet completely characterized Complexity in the action of glutamine on gene transcription Because glutamine is the most abundant amino acid in plasma and human skeletal muscle, a number of studies recently explored its mode of action on gene expression, revealing the existence of a large variety of target genes involved in major functions in the organism [15,82,83] Tables and and Fig illustrate both the diversity of the studies into the effect of glutamine and the variety of transcription factors involved in its action Although glutamine deprivation was also able to stimulate the expression of ASNS [84,85] and CHOP [86] genes in different kinds of mammalian cells, the involvement of the NSRE and AARE sequences in these effects was not studied Moreover, none of these responsive elements were identified in the other target genes studied The only putative AARE identified in a glutamine-responsive gene was found in the promoter of the glutamine transporter ASCT2 gene, but its involvement in the regulation by Table Influence of glutamine on transcription factors involved in inflammation Glutamine Experimental model Transcription factor(s) involved Deprivation Deprivation Human breast cancer cells Human intestinal (Caco-2) cells NF-jB and AP-1 STAT-4 Addition Addition Deprivation AP-1 (c-jun) PPAR-c NF-jB Addition Addition Addition Addition Addition Rat jejunum in vivo Postischaemic rat intestine Human fetal intestinal cell line (H4) and Caco-2 cells Irradiated rat ileum in vivo Rat colon (and pancreas) in vivo (experimental colitis) Human intestinal (HTC-8) cells human intestinal (Caco-2) cells Rat colon in vivo (experimental colitis) Rat intestine in vivo (brain trauma injury) Rat colon in vivo (experimental colitis) Addition Addition Adipose tissue in high fat diet rat Rat lung in vivo NF-jB NF-jB NF-jB NF-jB NF-jB and STATs NF-jB NF-jB Addition Addition Addition Addition Addition Mouse lung in vivo (LPS-treatment) LPS-treated rat alveolar epithelial cells Septic mouse lung in vivo Septic mouse lung in vivo Mouse embryonic fibroblasts (HSF)/)) NF-jB NF-jB NF-jB HSF-1 and Sp1 HSF-1 Addition Addition NF-jB NF-jB Effect and mechanism involved Increased DNA binding Increased DNA binding and nuclear protein level Decreased DNA binding Increased DNA binding Decreased IjBa level; increased p65 binding and nuclear protein level Decreased protein amount Decreased protein amount Increased IjBa level Decreased DNA binding and nuclear p65 amount Increased IkB Protein and decreased p65 protein Decreased DNA binding and p65 protein level Decreased nuclear p50 and p65 levels and phosphorylated STAT1 and STAT5 Decreased IKKb and decreased p65 binding Increased IjBa expression and decreased p65 binding Decreased LPS-induced DNA binding Decreased LPS-induced DNA binding Decreased DNA binding activation Increased O-glycosylation and phosphorylation Activation FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works Reference [90] [91] [78] [61] [92] [94] [95] [93] [44] [96] [98] [97] [99] [100] [101] [102] [113] [111] [112] 1831 Glutamine and transcription factors C Brasse-Lagnel et al Table Influence of glutamine on transcription factors involved in cell proliferation, apoptosis and survival Transcription factor(s) involved Glutamine Experimental model Addition Addition Porcine enterocyte line Rat and pig intestinal cell lines Addition Induced rat mammary tumours Deprivation Addition Addition Deprivation Deprivation Addition Deprivation Murine hybridoma cells Exercised rat neutrophils Pig renal epithelial cell line Human breast cells CHO cells Murine hybridoma cells Human lung carcinoma cells Deprivation Addition Addition Human pancreatic and prostatic cancer cells Rat heat-shocked intestinal cell line Mouse embryonic fibroblasts Addition Addition Deprivation Addition Rat intestine in vivo Mouse fibroblasts (HSF)/)) Human carcinoma cells Pancreatic b-cell line p53 p53 CHOP CHOP and Gadd 45 CHOP CHOP HIF-1a/2a, Gadd 34 and CHOP HIF-1a HSF-1 HSF-1 Reference Increased mRNA level Increased mRNA levels and increased c-jun activity Increased p53 phosphorylation and decreased c-myc mRNA level Decreased mRNA level Decreased exercise-induced mRNA level Decreased mRNA level Increased mRNA stabilization Increased mRNA level Decreased mRNA and protein levels Decreased HIF-1/2 a protein, increased Gadd 34 and CHOP mRNA levels Decreased protein level c-jun AP-1 (c-jun) and c-myc p53 and c-myc [123] [124] Increased DNA binding Increased phosphorylated nuclear HSF-1 and DNA binding Increased protein level Activation Increased mRNA stabilization Increased mRNA level and DNA binding HSF-1 HSF-1 ATF5 Pdx1 GAPDH GCACGTAGC Effect and mechanism involved [139] [131] [151] [86] [134] [132] [135] [133] [153] [143] [144] [146] [145] [136] [126] ADSS1 CRE –126 –118 CREM C/EBP α, β PKA mTOR Rat cardiomyocytes HepG2 cells Glutamine FXR Hexosamine pathway Sp1 glycosylation RXR/FXR Sp1 AGGTGAATGACTT –586 –574 HepG2 cells ASS ASCT2 GC boxes Caco-2 cells the amino acid in HepG2 cells was not demonstrated [87] Interestingly, studies on the glutamine-responsive genes and the involved transcription factors revealed some functional categorization corresponding to 1832 Fig Schematic representation of the influence of glutamine on the transcription of genes involved in intermediary metabolism specific effects of the amino acid in: (a) the inflammatory response; (b) cell proliferation, differentiation and survival; and (c) metabolic functions We therefore attempted to delineate the contribution of the gluta- FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works C Brasse-Lagnel et al mine-modulated transcription factors within each category NF-jB and the effect of glutamine in the inflammatory response (Table 4) It is well known that glutamine is able to exert local and systemic immunoregulatory activity [88,89] In particular, the anti-inflammatory role of glutamine has been extensively studied both in vivo and in vitro, and data obtained on the regulation of cytokine production by the amino acid led to demonstration of the involvement of specific transcription factors, mainly NF-jB Indeed, in glutamine-deprived human breast cancer cells, activation of NF-jB DNA-binding may account in part for increased expression of the IL-8 gene [90] In addition to STAT [91], the amino acid was shown to act at the level of the inhibitor of kappa B (IjB) because, in lipopolysaccharide (LPS)-treated Caco-2 cells, glutamine deprivation decreased the level of IjB-a leading to an increase in NF-jB within the nucleus [92] In line with this, addition of glutamine to HTC-8 cells was shown to increase the IjBa content by limiting its ubiquitination [93] In addition, glutamine might also act via a decrease in NF-jB synthesis or an increase in its degradation because administration of the amino acid decreased the immunoreactive NF-jB protein in the intestine of injured rats [94,95] More recently, we demonstrated that glutamine addition was able to decrease the nuclear content of p65 NFjB within h, in control or cytokine-stimulated Caco-2 cells [44] Finally, in an experimental model of colitis in the rat, glutamine administration not only prevented the decrease in IjBa and the subsequent increase in nuclear p65, but also prevented the increase in IjB kinases (IKKa and IKKb), thereby reducing the production of pro-inflammatory mediators [96,97] This was also reported in rat intestine following brain trauma injury [98] and adipose tissue following high fat diet [99] Such studies were also performed in septic rat lung in vivo, where glutamine inhibited IjB-a degradation resulting in the attenuation in tumour necrosis factor (TNF)-a and IL-6 production In this condition, the amino acid was shown to interfere with the NF-jB pathway through the inhibition of p38 MAPK and ERK phosphorylation [100] In septic mouse lung, glutamine administration before LPS injection also decreased NF-jB activation and subsequent TNF-a production [101] This was recently demonstrated in vitro in LPS-stimulated rat alveolar cells in which addition of glutamine increased the glutathione level, prevented Glutamine and transcription factors NF-jB activation and attenuated TNF-a release [102] Taken together, these results highlight the physiological importance of glutamine which, by counteracting activation of the NF-jB pathway, contributes to the attenuation of local inflammation in the gut and lung The pathway by which glutamine attenuates NF-jB activation is not yet clear although it may involve enhanced intracellular glutathione in turn inhibiting NF-jB activation [103] or an increase in the O-linked N-acetylglucosamine protein levels [104] In line with these observations, glucosamine, a metabolite of glutamine, was also shown to exert anti-inflammatory properties through the inhibition of the IL-1b-induced activation of NF-jB in cultured rat or human chondrocytes [105,106] and in TNF-astimulated human retinal cells [107] Furthermore, glucosamine was recently reported to suppress the LPS-induced production of NO via a decrease in the expression of iNOS by inhibiting NF-jB activation and phosphorylation of p38 MAP kinase in mouse macrophages [108] However, this effect might be tissue-specific because glucosamine remained without any effect on the IL-1b-induced NF-jB pathway in Caco-2 cells [44] and could even activate NF-jB in mesangial cells [109] In addition to its influence on NF-jB and consistent with its role as an anti-inflammatory molecule, a protective effect of glutamine in injured intestine was also observed via the inhibition of the DNAbinding activity of AP-1 [78] This was mediated by the stimulation of peroxisome proliferator-activated receptor c (PPAR-c) [61,110] and also through a decrease in the phosphorylated form of STAT1 and STAT5 [97] Also contributing to its anti-inflammatory action, the amino acid could induce the heat shock protein response involving the O-glycosylation and phosphorylation of the heat shock factor-1 (HSF-1) [111] Notably, glutamine addition could attenuate cytokine-induced NO production only in HSF-1+/+ mouse embryonic fibroblasts, the effect being lost in HSF-1)/) cells [112] In this regard, the attenuation of NF-jB activation, the inhibition of proinflammatory cytokine production and the subsequent decrease in lung injury following glutamine treatment were lost in Hsp70()/)) mice [113] Collectively, these data show that glutamine exerts anti-inflammatory effects through several pathways, at least in part through the inhibition (NF-jB, AP-1 and STAT) or activation (PPAR-c and HSF-1) of specific transcription factors Moreover, the anti-inflammatory effects of glutamine are tightly linked to the mechanisms of cell survival, as discussed below FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works 1833 Glutamine and transcription factors Transcription factors involved in the regulatory role of glutamine on cell proliferation, apoptosis and survival Different effects on cellular processes may contribute to the trophic role of glutamine, namely an increase in protein and nucleotide synthesis [114,115], a decrease in proteolysis [116], reinforcement of the mitogenic action of growth factors like epidermal growth factor or growth hormone [117–120] and inhibition of apoptosis [121,122] (Table 5) Some of these actions were shown to be exerted partly through the synthesis or/ and activation of specific transcription factors in various kinds of cells For example, in a porcine jejunal cell line, glutamine addition was followed by rapid stimulation of the immediate early gene c-jun expression, followed by an increase in mRNA and protein levels of ornithine decarboxylase leading to subsequent induction of the polyamine synthesis [123] This was also reported in rat and pig intestinal cell lines in which expression of factors c-myc and c-jun, both involved in cellular proliferation and differentiation, was stimulated by glutamine addition, accounting for the important contribution of the amino acid to cellular growth [124] Concerning the signalling pathways involved in the proliferative effect of glutamine on enterocytes, the amino acid was shown to activate two classes of MAP kinase, the ERKs and the c-Jun N-terminal kinase (JNK) [125] Through ERK signalling, glutamine was shown to specifically stimulate MEK-1, the upstream kinase that activates ERK-1 and ERK-2, leading to subsequent phosphorylation of transcription factor Elk-1 involved in cellular differentiation Through JNK signalling, the increased expression of c-jun gene by glutamine led to the subsequent activation of factor AP-1 involved in cell proliferation The metabolism of glutamine was required to activate the requested regulatory protein kinases but the underlying mechanism remains unidentified [125] In parallel, glutamine could also stimulate specific cell differentiation as shown by microarray analysis in a pancreatic b-cell line revealing multiple gene changes with a particular stimulation of the Pdx1 that is essential for pancreatic b-cell differentiation and function [126] By contrast, glutamine addition downregulated some genes encoding factors involved in the inhibition of proliferation or in protein degradation and apoptosis [127,128] Indeed, its inhibiting effect on specific caspase activity protects against DNA breakage in various tissues, but the underlying molecular mechanisms are not yet fully understood [121,122,129–131] Nevertheless, the inhibiting effect of glutamine on transcription 1834 C Brasse-Lagnel et al factors involved in the cessation of growth, such as CHOP, was clearly demonstrated in a number of studies For example, glutamine addition partly suppressed the expression of CHOP mRNA in pig renal epithelial cells lowering growth-cessation signals [86] Conversely, depletion of the amino acid induced activation of CHOP gene expression in Chinese hamster ovary cells increasing cell death [132] and induced a parallel increase in CHOP and GADD 34 mRNA levels in hepatocarcinoma cells in favour of cancer cell death [133] Such a stimulation of CHOP and GADD 45, another growth-inhibiting gene, was obtained following glutamine depletion in human breast cell lines, decreasing their growth and viability, an effect occurring mainly at a post-transcriptional level [134] Two different lines of approach using murine hybridoma cells showed that glutamine has an anti-apoptotic effect One study demonstrated that addition of glutamine to the culture medium limited cell death via a negative control on CHOP gene expression [135], whereas the other study showed that its removal increased cell death through the regulation of several genes, namely a decrease in the tumour suppressor p53 mRNA level and a parallel stimulation in the expression of receptor FAS [131] In parallel, glutamine could also had an anti-apoptotic role in HeLaS3 cells through the destabilization of ATF5 mRNA, a transcription factor involved in cellular differentiation and apoptosis [136] Glutamine was also able to counteract the effects of c-myc, a transcription factor involved in proliferation and apoptosis, conducting paradoxically either to a reduction or to a stimulation of the apoptosis process, depending mainly on the level of c-myc expression and on the cell type Indeed, glutamine addition could protect cells from apoptosis induced by c-myc overexpression, as reported in human hepatoma cell line [137] and inversely, glutamine deficiency could induce apoptosis through an increase in the MYC protein level in different human cell lines [138] In rat mammary tumours, the dietary amino acid also counteracted the proliferative effect of c-myc by reducing its phosphorylation and mRNA level and by stimulating phosphorylation of p53, leading to tumour reduction [139] Thus, in experimental breast cancer, dietary glutamine could paradoxically promote the process of apoptosis This was reported to be the result of glutathione downregulation [140,141] These results illustrate the complex regulation exerted by glutamine on transcription factor such as c-myc, i.e the activation of its gene expression in enterocyte lines in favour of proliferation, as pointed out above [124], and its inhibition in some tumours and other cell lines limiting proliferation FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works C Brasse-Lagnel et al In the context of heat shock, an anti-apoptotic effect of glutamine was also exerted via the stimulation of Hsp protein production, both at transcriptional and post-transcriptional levels [103,142] Concerning its transcriptional effect, activation of nuclear factor HSF-1 and binding to a heat shock element (HSE) resulting in the transcription of Hsp genes was reported in rat intestinal cells and mouse fibroblasts [143–146] In particular, heat stress injury was improved by glutamine treatment in wild-type mouse embryonic fibroblasts (HSF-1+/+) although in knockout cells (HSF-1)/)), the beneficial effect of glutamine on survival was lost [112] Activation of HSF-1 by glutamine was also demonstrated in rat intestine in vivo improving survival after hyperthermia [146] Lastly, HSF-1 was also proposed to be involved in the glutamine-induced expression of Hsp72 in the liver of rat submitted to heat shock [147] Several signalling pathways were reported to be involved in the anti-apoptotic effect of glutamine [82,148] but data remain sparse For example, the amino acid was shown to facilitate the inhibition of apoptosis signal-regulating kinase (ASK1) in HeLa cells, thereby limiting apoptosis and providing one possible explanation for the anti-apoptotic activity of glutamine [149] In addition, glutamine may activate the ERK signalling pathway in rat intestinal epithelial cells, preventing apoptosis, although JNK and p38 activities were not modified [150] However, glutamine was shown to partially prevent the increase in p38 and JNK phosphorylation in rat neutrophils, thereby reducing apoptosis induced by exercise [151] This underlines the complex regulation exerted by glutamine on signalling pathways such as the MAP kinases, i.e JNK activation in enterocytes [125] and inhibition in exercised rat neutrophils, depending on the cell type and physiological condition Taken together, the data show that glutamine is able to promote cell growth, attenuate the pathological stress response and modulate apoptosis, at least partly through the activation of specific transcription factors These observations have led to proposals that the amino acid is a ‘survival factor’ However, glutamine was also reported to act in the context of hypoxia, a situation known to stimulate transcription factor hypoxia-inducible factor-1 (HIF-1) HIF-1 is involved in the maintenance of oxygen homeostasis, angiogenesis and hence, in tumour progression [152] Indeed, studies performed on human carcinoma cells showed that glutamine deprivation decreased HIF-1a and HIF-2a with an impaired release of vascular endothelial growth factor (VEGF-A, a prominent mediator of angiogenesis), limiting tumour oxygenation and Glutamine and transcription factors favouring cancer cell death [133] Furthermore, glutamine deprivation was also able to inhibit the hypoxiainduced HIF-1a protein at the translational level in human pancreatic and prostatic cancer cells [153] Transcription factors involved in the regulatory role of glutamine on intermediary metabolism In parallel to its role as a metabolic substrate, glutamine also stimulates a number of metabolic pathways, namely hepatic lipid formation and glycogen synthesis [154], hepatic and renal gluconeogenesis [155], and muscle protein synthesis [156] About 12 years ago, the expression of some genes encoding enzymes directly or indirectly involved in the metabolism of amino acids was shown to be stimulated by glutamine in the liver and intestine For example, in rat liver, glutamine stimulated the expression of PEPCK, glutamine synthetase [157,158] and ASS genes [159], and these effects were shown to be mediated, at least in part, by glutamineinduced cell swelling [160] Glutamine might regulate its own synthesis by interacting at the transcriptional and post-transcriptional levels with the 3¢-UTR of the glutamine synthetase gene but the regulatory factors involved are not yet identified [161] Several reports brought about some characterization of the molecular mechanisms involved in the glutamine action on genes related to metabolism, as summarized in Fig A first study was performed in HepG2 hepatoma cells where glutamine stimulated transcription of the GAPDH gene [162] Using deletion mutants and site-directed mutagenesis of the GAPDH promoter, it was shown that glutamine responsiveness is mediated by a specific sequence (-126/-118) which could bind C/EBP proteins The corresponding binding cis element was not specified further but the metabolism of glutamine was found to be required in this effect In a second study performed in cultured rat cardiomyocytes, glutamine was shown to stimulate the expression of CPT1 and ADSS1 [163], encoding enzymes involved in cardiac fatty acid metabolism and adenine nucleotide metabolism, respectively Induction was mediated via the protein kinase A pathway and partly through that of mammalian target of rapamycin, which is known to be regulated by growth factors and nutritional status, particularly amino acid availability [164] Thus, the ADSS1 response to protein kinase A and mammalian target of rapamycin signalling subsequently involved phosphorylation of the cAMP response element modifier and its binding to a cAMP response element in the promoter region of the ADSS1 gene [163] A third study performed by our group showed that glutamine addition increased ASS gene transcription in human FEBS Journal 276 (2009) 1826–1844 Journal compilation ª 2009 FEBS No claim to original French government works 1835 Glutamine and transcription factors enterocytes [165] but, by contrast to the results obtained in hepatocytes [159], cell swelling was not involved in the effect of the amino acid Indeed, we demonstrated that glutamine metabolism was involved in Sp1 O-glycosylation via the hexosamine pathway This post-translational event induced the subsequent nuclear translocation of Sp1 and its binding to GC boxes in the promoter of the ASS gene [165] Moreover, via another pathway, namely glutamate production, glutamine was able to mask the stimulating effect of IL-1b on ASS gene expression via a decrease in the nuclear amount of NF-jB [44] This illustrates that glutamine may regulate expression of the same gene via different pathways as a function of cell type and pathophysiological conditions In addition to its effect on the ASS gene, glycosylation of Sp1 can also stimulate the ClC-2 gene expression, as observed after glutamine addition to rat lung cell lines [166] In addition, increased expression of phosphorylated Sp1 after the blockade of glutamine metabolism was observed in Ehrlich tumour cells [167] Finally, in a study performed in HepG2 hepatoma cells, glutamine was shown to activate the nuclear farnesoid X receptor (FXR)/retinoid X receptor (RXR), favouring its binding to its responsive sequence in the promoter of the ASCT2 gene encoding a glutamine transporter [168,169] Together, these studies illustrate that different transcription factors, namely C/EBP, FXR/RXR, cAMP response element modifier and Sp1, and their corresponding responsive elements are required to regulate various metabolic pathways in the hepatic, cardiac and intestinal transcriptional response to glutamine These responsive cis elements are not specific of an AAR pathway suggesting that the effects of glutamine and potentially those of other amino acids might depend not only on cell types but also on the structure of the gene promoters Finally, Fig summarizes the different families of transcription factors modulated by glutamine to regulate physiological processes Moreover, considering the effects of other amino acids (independently of the cell types and the target genes), the figure highlights that some amino acids may act similarly to glutamine, some others exerting the opposite effect Concluding remarks In summary, regulation of transcription by amino acids appears to derive from a variety of mechanisms Indeed, since the initial reports identifying specific AARE/NSRE sequences and ATF factors involved in the effects of amino acids on gene transcription, a 1836 C Brasse-Lagnel et al Fig Families of transcription factors modulated by glutamine to regulate physiological processes Comparison with the effects of other amino acids The families of transcription factors modulated by glutamine are written in coloured characters depending on its effect: red, inhibition; green, activation; grey, inhibition or activation depending on the cell types or the experimental conditions The effects of the other amino acids (circle connected by a line) are presented by using the same colours number of studies have reported that a variety of transcription factors, much larger than initially thought, can be modulated by amino acids with major functional implications This is particularly illustrated by glutamine, which has received increased attention in recent years and turned out to be an important regulator of gene expression without any evidence for a ‘glutamine-responsive element’ Microarray techniques [126,170,171] and proteomic studies [172–174] are now identifying the extent of the genetic programme controlled by glutamine and the underlying molecular mechanisms are being extensively deciphered The emerging data show that cells have developed various molecular mechanisms to respond to changes in extracellular glutamine concentrations Indeed, through the activation of different signalling pathways (ERK, JNK, PKA and mTOR pathways) and a variety of transcription factors including bZIP proteins (ATFs, C/EBP), helix–turn–helix proteins (HSF-1), zinc fingers proteins (Sp1) and nuclear receptors (PPAR, FXR/ RXR), glutamine significantly contributes to the regulation of genes involved in major cellular processes, namely the inflammatory response, proliferation, survival and metabolism Moreover, glutamine modulates the activity of transcription factors at multiple levels, i.e synthesis or degradation, posttranslational modifications or modulation of their activators 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C/EBP factors in the inhibiting effect of amino acids on gene expression Concerning the stimulation of gene expression by the presence of amino acids, only one gene, Pept 1, encoding a peptide transporter,... presence of amino acid(s) resulted in inhibition of the DNA binding of the involved transcription factors By contrast, the presence of amino acid may also result in stimulation of the DNA binding of. .. action of glutamine on gene transcription Because glutamine is the most abundant amino acid in plasma and human skeletal muscle, a number of studies recently explored its mode of action on gene expression,