Differences in the Molecular Mechanisms Involved in the Transcriptional Activation of the CHOP and Asparagine Synthetase Genes in Response to Amino Acid Deprivation or Activation of the Unfolded Protein Response

Bruhat, Alain; Avérous, Julien; Carraro, Valérie; Zhong, Can; Reimold, Andreas M.; Kilberg, Michael S.; Fafournoux, Pierre

doi:10.1074/jbc.m206149200

Cited by 72 publications

(68 citation statements)

References 39 publications

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“…response elements nor nutrient-sensing response elements could be identified on the ASS proximal promoter (17) in contrast to CHOP (C/EBP homology protein) and asparagine synthase genes (27,28). Additionally, a number of transcription factors, namely activator protein-1 (AP-1 (29)), hepatocyte nuclear factor-1 (HNF-1 (30)), activating transcription factor-4 (ATF-4) (28) and -2 (31), and C/EBP␤ (32), were also involved in the regulation of the expression of genes by amino acids, but again the responsive elements to these transcription factors were not identified on the ASS gene promoter.…”

Section: Discussionmentioning

confidence: 99%

Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

Brasse‐Lagnel

Fairand

Lavoinne

et al. 2003

Journal of Biological Chemistry

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Glutamine stimulates the expression of the argininosuccinate synthetase (ASS) gene at both the level of enzyme activity and mRNA in Caco-2 cells. Searching to identify the pathway involved, we observed that (i) the stimulating effect of glutamine was totally mimicked by glucosamine addition, and (ii) its effect but not that of glucosamine was totally blocked by 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of amidotransferases, suggesting that the metabolism of glutamine to glucosamine 6-phosphate was required. Moreover, run-on assays revealed that glucosamine was acting at a transcriptional level. Because three functional GC boxes were identified on the ASS gene promoter (

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Section: Discussionmentioning

confidence: 99%

Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

Brasse‐Lagnel

Fairand

Lavoinne

et al. 2003

Journal of Biological Chemistry

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“…We therefore propose that the cat-1 promoter contains a separate ER response element. The CHOP gene also has different promoter elements that regulate transcription during amino acid starvation and ER stress (16,17). Induction of CHOP transcription by ER stress requires an ATF composite site, which is involved in amino acid control, and a second element that is unique to ER stress (17).…”

Section: Discussionmentioning

confidence: 99%

“…In yeast, amino acid starvation stimulates the transcription of many genes by a well characterized mechanism involving the regulator GCN4 (14). The situation is less well studied in mammalian cells, with only two genes, asparagine synthetase (AS) and C/EBP homologous protein (CHOP), studied in detail at the molecular level (15)(16)(17). The transcription of these genes is stimulated by both amino acid starvation and the UPR.…”

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confidence: 99%

“…The transcription of these genes is stimulated by both amino acid starvation and the UPR. The promoter regions of these genes contain an amino acid response element (AARE) in their 5Ј-untranslated regions that is required for the enhanced transcription during cellular stress (16). The stress-induced transcription of both of these genes has been associated with phosphorylation of eIF2␣.…”

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confidence: 99%

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Transcriptional Control of the Arginine/Lysine Transporter, Cat-1, by Physiological Stress

Fernandez¹,

Lopez²,

Wang³

et al. 2003

Journal of Biological Chemistry

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Cells respond to physiological stress by phosphorylating the ␣ subunit of the translation initiation factor eIF2. This adaptive response inhibits protein synthesis and up-regulates genes essential for cell survival. Cat-1, the transporter for the essential amino acids, arginine and lysine, is one of the up-regulated genes. We previously showed that stress increases cat-1 expression by coordinated stabilization of the mRNA and increased mRNA translation. This induction is triggered by amino acid depletion and the unfolded protein response (UPR), which is caused by unfolded proteins in the endoplasmic reticulum. We show here that cat-1 gene transcription is also increased by cellular stress. Our studies demonstrate that the cat-1 gene promoter/regulatory region is TATA-less and is located in a region that includes 94 bases of the first exon. Transcription from this promoter is stimulated 8-fold by cellular stress. An amino acid response element within the first exon is shown to be required for the response to amino acid depletion but not to the UPR. The stimulation of transcription by amino acid depletion requires activation of GCN2 kinase, which phosphorylates eIF2␣. This phosphorylation also induces translation of the cat-1 mRNA, demonstrating that stress-induced transcriptional and translational control of cat-1 are downstream targets of a signaling pathway initiating with eIF2␣ phosphorylation. Our studies show that the increase in cat-1 gene expression by cellular stress involves at least three types of coordinate regulation: regulation of transcription, regulation of mRNA stability, and regulation of mRNA translation.

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“…This modulation may involve the activation of specific intracellular pathways involved in protein synthesis, including activation of the mammalian target of rapamycin (mTOR) pathway. It has been observed that mTor responds immediately to any modification in aminoacid or energy consumption (Bruhat et al, 2002;Asnaghi et al, 2004). When aminoacid storage, particularly leucine, is elevated, mTOR interacts with other proteins to form protein complexes in order to phosphorylate their key-components, which are in turn responsible for translating mRNA into proteins.…”

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confidence: 99%

Protein synthesis regulation by leucine

Vianna

Teodoro

Leal

et al. 2010

Braz. J. Pharm. Sci.

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In vivo and in vitro studies have demonstrated that high protein diets affect both protein synthesis and regulation of several cellular processes. The role of amino acids as substrate for protein synthesis has been established in the literature. However, the mechanism by which these amino acids modulate transcription and regulate the mRNA translation via mTOR-dependent signaling pathway has yet to be fully determined. It has been verified that mTOR is a protein responsible for activating a cascade of biochemical intracellular events which result in the activation of the protein translation process. Of the aminoacids, leucine is the most effective in stimulating protein synthesis and reducing proteolysis. Therefore, it promotes a positive nitrogen balance, possibly by favoring the activation of this protein. This amino acid also directly and indirectly stimulates the synthesis and secretion of insulin, enhancing its anabolic cellular effects. Therefore, this review aimed to identify the role of leucine in protein synthesis modulation and to discuss the metabolic aspects related to this aminoacid. Uniterms:Leucine. Protein synthesis. Transcription Factors. mTOR. Translation Protein.Estudos in vivo e in vitro verificaram que dietas hiperprotéicas influenciam a síntese protéica e regulam vários processos celulares. O papel dos aminoácidos como substrato para a síntese de proteínas já está bem evidenciado na literatura, porém as formas como esses aminoácidos modulam a etapa da transcrição e regulam a tradução do RNAm, pela via de sinalização dependente da mTOR, ainda não estão totalmente esclarecidas. Tem-se verificado que a mTOR é uma proteína responsável por ativar uma cascata de eventos bioquímicos intracelulares que culminam na ativação do processo de tradução protéica. Dentre todos os aminoácidos, a leucina é a mais eficaz em estimular a síntese protéica, reduzir a proteólise e, portanto, favorecer o balanço nitrogenado positivo, possivelmente por favorecer a ativação desta proteína. Além disso, este aminoácido estimula direta e indiretamente a síntese e a secreção de insulina, e, assim, aumenta as propriedades anabólicas celulares. Nesse sentido, a presente revisão tem como objetivo identificar o papel da leucina na modulação da síntese protéica e abordar aspectos metabólicos relacionados a este aminoácido.Unitermos: Leucina. Síntese protéica. Fator de transcrição. mTOR. Tradução de proteínas. INTRODUCTIONProtein synthesis in tissue is rapidly stimulated after nutrient consumption. Insulin and aminoacids stimulate protein anabolism, acting in a posterior step of gene transcription, i.e., on protein translation. However, the mechanism by which the aminoacids stimulate protein translation has yet to be fully determined (Proud, 2002).Some studies have verified that high-protein diets stimulate protein synthesis. Some of the benefits promoted by this diet on body composition can be attributed to high consumption of branched-chain aminoacids (BCAA), which include the aminoacids leucine, valine and isoleucine (Donato...

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Differences in the Molecular Mechanisms Involved in the Transcriptional Activation of the CHOP and Asparagine Synthetase Genes in Response to Amino Acid Deprivation or Activation of the Unfolded Protein Response

Cited by 72 publications

References 39 publications

Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

Glutamine Stimulates Argininosuccinate Synthetase Gene Expression through Cytosolic O-Glycosylation of Sp1 in Caco-2 Cells

Transcriptional Control of the Arginine/Lysine Transporter, Cat-1, by Physiological Stress

Protein synthesis regulation by leucine

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