Induction of CHOP Expression by Amino Acid Limitation Requires Both ATF4 Expression and ATF2 Phosphorylation

The CHOP gene is transcriptionally induced by amino acid starvation. We have previously identified a genomic cis-acting element (amino acid response element (AARE)) involved in the transcriptional activation of the human CHOP gene by leucine starvation and shown that it binds the activating transcription factor 2 (ATF2). The present study was designed to identify other transcription factors capable of binding to the CHOP AARE and to establish their role with regard to induction of the gene by amino acid deprivation. Electrophoretic mobility shift assay and transient transfection experiments show that several transcription factors that belong to the C/EBP or ATF families bind the AARE sequence and activate transcription. Among all these transcription factors, only ATF4 and ATF2 are involved in the amino acid control of CHOP expression. We show that inhibition of ATF2 or ATF4 expression impairs the transcriptional activation of CHOP by amino acid starvation. The transacting capacity of ATF4 depends on its expression level and that of ATF2 on its phosphorylation state. In response to leucine starvation, ATF4 expression and ATF2 phosphorylation are increased. However, induction of ATF4 expression by the endoplasmic reticulum stress pathway does not fully activate the AARE-dependent transcription. Taken together our results demonstrate that at least two pathways, one leading to ATF4 induction and one leading to ATF2 phosphorylation, are necessary to induce CHOP expression by amino acid starvation. This work was extended to the regulation of other amino acid regulated genes and suggests that ATF4 and ATF2 are key components of the amino acid control of gene expression. The CHOP gene is transcriptionally induced by amino acid starvation. We have previously identified a genomic cis-acting element (amino acid response element (AARE)) involved in the transcriptional activation of the human CHOP gene by leucine starvation and shown that it binds the activating transcription factor 2 (ATF2). The present study was designed to identify other transcription factors capable of binding to the CHOP AARE and to establish their role with regard to induction of the gene by amino acid deprivation. Electrophoretic mobility shift assay and transient transfection experiments show that several transcription factors that belong to the C/EBP or ATF families bind the AARE sequence and activate transcription. Among all these transcription factors, only ATF4 and ATF2 are involved in the amino acid control of CHOP expression. We show that inhibition of ATF2 or ATF4 expression impairs the transcriptional activation of CHOP by amino acid starvation. The transacting capacity of ATF4 depends on its expression level and that of ATF2 on its phosphorylation state. In response to leucine starvation, ATF4 expression and ATF2 phosphorylation are increased. However, induction of ATF4 expression by the endoplasmic reticulum stress pathway does not fully activate the AARE-dependent transcription. Taken together our results demonstrate that at least two pathways, one leading to ATF4 induction and one leading to ATF2 phosphorylation, are necessary to induce CHOP expression by amino acid starvation. This work was extended to the regulation of other amino acid regulated genes and suggests that ATF4 and ATF2 are key components of the amino acid control of gene expression. All cells regulate gene expression in response to changes in the external environment such as nutrients availability. In mammals, plasma concentrations of nutrients are markedly affected by dietary or pathological conditions. The concentration of amino acids in the plasma is particularly sensitive to the nutritional state, with levels falling severalfold in cases of malnutrition. This may occur in response to a global limitation in protein intake or in response to specific limitations in essential amino acids (1Young V.R. El-Khoury A.E. Melchor S. Castillo L. Niels C.R.R Protein Metabolism During Infancy. Vol. 33. Nestec Ltd., Vevey/Raven Press, Ltd., New York1994: 1-28Google Scholar, 2Gietzen D.W. Leung P.M.B. Castonguay T.W. Hartmann W.J. Rogers G.R. Kare M.R. Brand J.G. Time Course of Food Intake and Plasma and Brain Amino Acid Concentrations in Rat Fed Amino Acid-imbalanced or -deficient Diet. Academic Press, New York1986: 415Google Scholar, 3Baertl J.M. Placko R.P. Graham G.G. Am. J. Clin. Nutr. 1974; 27: 733-742Crossref PubMed Scopus (52) Google Scholar). The current understanding of mechanisms involved in amino acid-dependent control of gene transcription has just begun to be clarified in mammalian cells (4Mordier S. Bruhat A. Averous J. Fafournoux P. Storey K.B. Storey J.M. Cell and Melrcular Response to Stress. 3 vols.. Elsevier, New York2002: 189-206Google Scholar, 5Fafournoux P. Bruhat A. Jousse C. Biochem. J. 2000; 351: 1-12Crossref PubMed Scopus (225) Google Scholar, 6Kilberg M.S. Barbosa-Tessmann I.P. J. Nutr. 2002; 132: 1801-1804Crossref PubMed Scopus (33) Google Scholar). At the molecular level, most of the results have been obtained by studying the transcriptional regulation of asparagine synthetase (AS) 1The abbreviations used are:ASasparagine synthetaseCHOPC/EBP homologous proteinNSREnutrient-sensing response elementATFactivating transcription factorAAREamino acid response elementERendoplasmic reticulumERSEER stress response elementDMEMDulbecco's modified Eagle's mediumCMVcytomegalovirusRTreverse transcriptasesiRNAsmall interference RNAHAThistone acetyl transferaseERKextracellular signal-regulated kinaseMAPKmitogen-activated protein kinaseJNKc-Jun NH2-terminal kinase.1The abbreviations used are:ASasparagine synthetaseCHOPC/EBP homologous proteinNSREnutrient-sensing response elementATFactivating transcription factorAAREamino acid response elementERendoplasmic reticulumERSEER stress response elementDMEMDulbecco's modified Eagle's mediumCMVcytomegalovirusRTreverse transcriptasesiRNAsmall interference RNAHAThistone acetyl transferaseERKextracellular signal-regulated kinaseMAPKmitogen-activated protein kinaseJNKc-Jun NH2-terminal kinase. and CHOP (C/EBP homologous protein, also called GADD153) gene expression in response to amino acid deprivation. asparagine synthetase C/EBP homologous protein nutrient-sensing response element activating transcription factor amino acid response element endoplasmic reticulum ER stress response element Dulbecco's modified Eagle's medium cytomegalovirus reverse transcriptase small interference RNA histone acetyl transferase extracellular signal-regulated kinase mitogen-activated protein kinase c-Jun NH2-terminal kinase. asparagine synthetase C/EBP homologous protein nutrient-sensing response element activating transcription factor amino acid response element endoplasmic reticulum ER stress response element Dulbecco's modified Eagle's medium cytomegalovirus reverse transcriptase small interference RNA histone acetyl transferase extracellular signal-regulated kinase mitogen-activated protein kinase c-Jun NH2-terminal kinase. AS is expressed in most mammalian cells and is responsible for the biosynthesis of asparagine from aspartate and glutamine. The level of AS mRNA increases in response to amino acid starvation (7Gong S.S. Guerrini L. Basilico C. Mol. Cell. Biol. 1991; 11: 6059-6066Crossref PubMed Scopus (80) Google Scholar, 8Guerrini L. Gong S.S. Mangasarian K. Basilico C. Mol. Cell. Biol. 1993; 13: 3202-3212Crossref PubMed Scopus (87) Google Scholar, 9Hutson R.G. Kilberg M.S. Biochem. J. 1994; 304: 745-750Crossref PubMed Scopus (64) Google Scholar). Barbosa-Tessmann et al. (10Barbosa-Tessmann I.P. Chen C. Zhong C. Siu F. Schuster S.M. Nick H.S. Kilberg M.S. J. Biol. Chem. 2000; 275: 26976-26985Abstract Full Text Full Text PDF PubMed Google Scholar) have identified, in the AS 5′-flanking region, two cis-elements termed nutrient-sensing response elements (NSRE-1, nt –68 to –60; NSRE-2, nt –48 to –43) that are essential for transcriptional activation by amino acid limitation. Electrophoretic mobility shift assay (EMSA) and overexpression of dominant negative mutants show that activation of the AS gene by amino acid limitation involves ATF-4 and C/EBPβ binding to the NSRE-1 site (11Siu F. Chen C. Zhong C. Kilberg M.S. J. Biol. Chem. 2001; 276: 48100-48107Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 12Siu F. Bain P.J. LeBlanc-Chaffin R. Chen H. Kilberg M.S. J. Biol. Chem. 2002; 277: 24120-24127Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). The CHOP gene a protein to the protein of transcription factors PubMed Scopus Google Scholar). of the C/EBP have been in the regulation of to and expression of genes S. PubMed Scopus Google Scholar, W.J. Nutr. 2001; PubMed Scopus Google Scholar). CHOP is induced by a of and Google Scholar, J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, H. A. R. Mol. Cell. Biol. PubMed Scopus Google Scholar). The regulation of CHOP mRNA expression by amino acid concentration has transcriptional and components A. Jousse C. Fafournoux P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). amino acid response element was and in the CHOP This element is to amino acid to a The sequence is to C/EBP and binding and was to bind in the activating transcription factor 2 in and conditions. the expression of ATF2 was shown to be essential for the transcriptional activation of CHOP by leucine starvation A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). CHOP and AS are also induced to level the endoplasmic reticulum stress by the of H. A. R. Mol. Cell. Biol. PubMed Scopus Google Scholar). The CHOP ER stress response element nt to from the AARE that the activation by ER stress H. K. H. K. Mol. Cell. Biol. 2000; PubMed Scopus Google and of the AS gene are involved in the response to amino acid starvation and ER stress (10Barbosa-Tessmann I.P. Chen C. Zhong C. Siu F. Schuster S.M. Nick H.S. Kilberg M.S. J. Biol. Chem. 2000; 275: 26976-26985Abstract Full Text Full Text PDF PubMed Google Scholar). the in the response to amino acid our is to the pathway from the amino acid response The to is to identify transcription factors capable of binding to the AARE of the CHOP and to establish their role with regard to induction of the gene by amino acid deprivation. is that several transcription factors that belong to the C/EBP or ATF families bind the AARE sequence and activate the AARE-dependent transcription. However, only ATF4 and ATF2 are involved in the amino acid regulation of CHOP expression. results demonstrate that at least two pathways, one leading to ATF4 induction and one leading to ATF2 phosphorylation, are necessary to induce CHOP expression by amino acid starvation. This work was extended to the regulation of other amino genes and suggests that ATF4 and ATF2 are key components of the amino acid control of gene expression. Cell and cells at in Dulbecco's modified Eagle's medium leucine was In all experiments amino acid starvation, was in ATF2 by A. of and in and by the as previously A. Jousse C. Fafournoux P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of was the cells with of a the gene to the human cytomegalovirus region, as In the experiments expression a of of expression and of was In the control the of was to 2 by of the the to be to the for in and with cells for in of and at for 2 of the was for was as previously F. J. Mol. Google Scholar). was as the of All are the from the results of at least from cells as previously A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). from of of to for and by to Electrophoretic mobility shift as previously A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). 2 of specific was to the at to the of the mobility shift was to the of the The of the ATF binding site PubMed Scopus Google and C/EBP binding site J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the for kinase to was as previously A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). was by one of the CHOP AARE sequence in the CHOP AARE sequence by the to was as previously A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). All the the and the to the The expression for and by S. and expression a control was by the of RNA was a and with to RNA was by RNA was with of reverse transcriptase to the for human in CHOP reverse AS reverse ATF2 reverse reverse reverse C/EBPβ reverse reverse reverse reverse reverse reverse and reverse for in and CHOP reverse AS reverse reverse reverse reverse reverse reverse and reverse used and in for mRNA mRNA was also for the human sequence reverse and for sequence reverse involved the of that been with specific of We the of the genes and the to the the of the sequence as in from to was a and in the a a of the components was to the of of of of reverse and 2 of was in the and of of was as and the The was for and for for and for with a with a of and a and a to negative control was with assay to the was used to in the to the from the of control results in of CHOP or AS of was to the of the and to ATF4 and and and mRNA designed as S.M. J. A. J. 2001; PubMed Scopus Google Scholar, S.M. 2001; PubMed Scopus Google Scholar). to ATF4 on and was used as a negative has a of 2 on RNA the to gene obtained from was as by S.M. J. A. K. 2001; PubMed Scopus Google the two in of 2 for at and for at transfection with cells in at 2 of was the cells the as The cells and in with was 2 the transfection in assay 2 acid from by and a for at with a of in The with in at to the The in and with in for at the the was from Cell and from and and by K. New and P. of to the C/EBP and ATF the CHOP AARE in previously identified a cis-acting element involved in the transcriptional activation of the human CHOP gene by leucine starvation and that it binds the activating transcription (ATF2). that other transcription factors that belong to the ATF and bind the AARE sequence together with of the C/EBP and these transcription factors for the CHOP AARE in the of specific the ATF and C/EBP AARE from to of the human CHOP was used as a from and previously A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google a specific is of and with CHOP AARE in the of specific in and that and the CHOP with and and the only with the a was obtained with the in the was as a from cells with a of the ER stress response and to a level of ATF4 expression H. R. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). shown ATF4 was obtained from and and not the and a control of leucine starvation on the C/EBP and ATF transcription factors cells in or in leucine for or RNA and was to as and of and of from cells in a for the of was from or from of on C/EBP and ATF in the binding of transcription factors to the AARE sequence from and cells suggests that the of these transcription factors is affected by leucine starvation. that the CHOP mRNA increases and a leucine starvation and A. Jousse C. Fafournoux P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the expression of the C/EBP and ATF transcription factors in response to and leucine starvation. that and mRNA is in response to leucine starvation, the expression level of other transcription factors is not is that the transcription factors and are expressed at a level in Protein that the expression of ATF4 and is markedly leucine starvation. The of ATF2 and C/EBPβ is not affected by leucine deprivation. The expression levels of and are to be by and protein was only in of the C/EBP and ATF in the Amino Acid of the AARE-dependent the transcription factors that bind the AARE sequence in regulate its transcriptional We a by the AARE sequence with that transcription of or the AARE-dependent expression the AARE-dependent transcription two of or does not The of these transcription factors to activate transcription is not to a of transfection of or in a of expression as by or We have also that transfection of of these expression not the AARE-dependent transcription not Among the transcription factors that bind the AARE sequence only and activate transcription. The was designed to their to the regulation of the AARE-dependent transcription by amino acid starvation. In a study A. Averous J. Zhong C. Kilberg M.S. Fafournoux P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) the the AARE essential for the transcriptional response to leucine starvation of the CHOP of mutants of the AARE sequence of the was to its response to leucine starvation and overexpression of one transcription that and are not to leucine starvation, are by overexpression of C/EBPβ or In these mutants are induced by ATF4 is that the and a response to leucine starvation, also a response to ATF4 Taken together these results show that is a at the level of the AARE the amino acid and the of ATF4 to activate the AARE-dependent transcription. a does not with C/EBPβ or results that ATF4 role in the amino acid regulation of the AARE of of ATF4 or on the Amino Acid of CHOP the role of ATF4 in the amino acid regulation of CHOP the of leucine starvation on CHOP mRNA and AARE-dependent transcription in We used small RNA transfection to the expression of that transfection the ATF4 protein and the response to leucine the induction of CHOP mRNA is and the AARE-dependent transcription is In control cells the response to leucine starvation is not demonstrate that ATF4 expression is essential for the regulation of CHOP expression by leucine starvation. Among the transcription factors to bind the AARE the AARE-dependent transcription has been that bind the CHOP in the of the AARE sequence and its transcription T.W. Biochem. J. PubMed Scopus Google Scholar, Chen Mol. Cell. Biol. PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar). has been shown that also regulate amino asparagine synthetase (AS) Chen H. Siu F. Kilberg M.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it a response on AS transcription. Taken together these to CHOP regulation by leucine starvation in In the in the response to leucine starvation in cells with The of does not the induction of CHOP mRNA by leucine starvation. The level of the AARE-dependent transcription is by the inhibition of the induction of transcription by leucine starvation is not Taken together these that does not essential role in the leucine control of CHOP expression. ATF4 to ER to the AARE-dependent results show that ATF4 essential role in the amino acid control of gene expression. ATF4 is also involved in the ER stress pathway H. R. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google the AARE of the ER stress In response to or leucine CHOP ATF4 protein and the transcriptional of the CHOP and the a concentration of and leucine starvation to the of the CHOP the ATF4 protein and the transcriptional of the CHOP the AARE-dependent transcription is induced only by leucine starvation Taken together these results show that ATF4 expression from a with a concentration of is not to activate the AARE-dependent transcription. ATF2 for the of the AARE-dependent have shown that ATF4 induction is not to activate the AARE transcription. We shown in a A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar) that CHOP is induced by leucine starvation in is also necessary to the AARE-dependent transcription. ATF2 is in response to its transcriptional as as its histone acetyl transferase are regulated by its phosphorylation on and S. PubMed Scopus Google Scholar, C. J. PubMed Scopus Google Scholar, H. A. P. P. J. PubMed Scopus Google Scholar, J. C. K. H. J. 2002; PubMed Scopus Google Scholar, H. L. R. K. K. 2000; PubMed Scopus Google Scholar). ATF2 is transcriptionally overexpression is not to activate transcription L. Biol. Chem. PubMed Scopus (33) Google and ATF2 activate the AARE in a used a of ATF2 the activation of ATF2 is with the transcriptional activation of ATF4 L. Biol. Chem. PubMed Scopus (33) Google Scholar). et al. L. Biol. Chem. PubMed Scopus (33) Google Scholar) that has the that the ATF2 in of for the binding site and the transfection experiments show that the AARE-dependent transcription the of ATF2 to the regulation of the AARE-dependent transcription by amino acid starvation, have the in 3 and the that the and are not to leucine starvation, are not induced by our results show that is a at the level of the AARE the amino acid and the of to activate the AARE-dependent transcription. the and ATF2 have L. Biol. Chem. PubMed Scopus (33) Google the binding of ATF2 on the previously mutants of the AARE has to be We a assay with the of the AARE sequence in and as a ATF2 binds the as as the and as shown by the of In the of the and are not to leucine starvation, was results demonstrate that the the CHOP AARE sequence to amino acid are also essential for the binding of ATF2 is by phosphorylation and is for the leucine regulation of CHOP it is amino acid starvation The of ATF2 was a specific the results in a and phosphorylation of ATF2 that starvation and to ATF4 and ATF2 in the of by Amino together our results demonstrate that leucine starvation two transcription factors that bind the it ATF4 expression and ATF2 the ATF2 and ATF4 of the amino acid regulation of gene expression is to CHOP or for other amino the expression of several genes regulated by amino acid in cells of ATF2 or ATF4 expression. Among the amino genes Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, S.M. J. Nutr. 2002; 132: PubMed Scopus Google genes expressed in cells and shown in and in with results Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, S.M. J. Nutr. 2002; 132: PubMed Scopus Google the mRNA for these genes was by amino acid starvation in control However, the induction level for asparagine synthetase induction by leucine starvation is in cells in The of ATF4 results in a or a of response to leucine starvation for all the genes of the cells that leucine regulation is for and AS and mRNA is not of ATF2 does not the leucine regulation of results show that ATF4 has a role in the leucine regulation of all the genes and ATF2 role for the leucine control of most of these The response element from the transcription site to is essential for the amino acid regulation of the CHOP of the CHOP AARE to the specific binding site of transcription factors that belong to the C/EBP and ATF However, have A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar) that several ATF or C/EBP binding are to the AARE are not to amino acid that a of transcription factors is to the amino acid We have previously that the transcription factor ATF2 in the CHOP AARE and is essential for the transcriptional activation of CHOP by leucine starvation. are to other transcription factors to bind the AARE sequence and involved in the amino acid regulation of CHOP expression and to the mechanisms involved in the activation of and have also the to bind the CHOP AARE sequence and to the regulation of transcription. However, our demonstrate that these transcription factors only ATF4 essential role in the amino acid control of CHOP expression. H. R. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) have a pathway for gene expression in mammalian cells that is homologous to the control response to amino acid Biochem. 1994; Full Text PDF PubMed Scopus Google Scholar). components by amino acid starvation and ATF4 to the transcription factor is the protein is present and the of CHOP regulation by amino acid are with the role of of a protein is to activation of CHOP transcription by leucine starvation A. Jousse C. Fafournoux P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with ATF4 expression is by amino acid deprivation. the binding of ATF4 on the AARE sequence is induced leucine starvation. ATF4 overexpression increases the AARE-dependent transcription. the AARE sequence that the amino acid also the transcriptional response to ATF4 of ATF4 gene the transcriptional activation of CHOP by amino acid starvation. In the ATF4 of the amino acid regulation of gene expression is not to CHOP for other amino The role of ATF4 in the regulation of CHOP expression the role of in experiments show that in ATF4 expression ER stress the AARE-dependent a ATF4 induction to leucine starvation the AARE that a amino acid-dependent other ATF4 to activate the AARE-dependent transcription. This the transcriptional of ATF4 its with its with its C. H. L. R. F. Mol. Cell. Biol. 2001; PubMed Scopus Google its A. F. A. S. A. 2000; PubMed Scopus Google Scholar). However, it is that overexpression of ATF4 the for amino acid-dependent transient transfection of results in a overexpression of the AARE The in with previously results A. Jousse C. Fafournoux P. Mol. Cell. Biol. 2000; PubMed Scopus Google demonstrate that ATF2 has essential role in the transcriptional activation of CHOP by leucine starvation. ATF2 binds its sequence as a or as a with a of other The transacting capacity of ATF2 depends on its phosphorylation on and and on its S. PubMed Scopus Google Scholar, C. J. PubMed Scopus Google Scholar, H. A. P. P. J. PubMed Scopus Google Scholar, J. C. K. H. J. 2002; PubMed Scopus Google Scholar, H. L. R. K. K. 2000; PubMed Scopus Google Scholar). show that ATF2 is on leucine starvation. to the ATF2 is on by the mitogen-activated protein kinase and protein kinase J. C. K. H. J. 2002; PubMed Scopus Google Scholar) in response to or or has been shown that and are not by starvation in a amino acid C. S. H. C. P. Cell 2001; 13: PubMed Scopus Google Scholar). However, the c-Jun kinase is induced by leucine starvation C. S. H. C. P. Cell 2001; 13: PubMed Scopus Google Scholar) with a of activation that the and phosphorylation of the kinase involved in the phosphorylation of ATF2 in response to leucine starvation to be ATF2 of the amino acid regulation of gene expression is to the ATF2 the leucine control of most of the the amino acid control of genes or to ATF2 expression. ATF2 has histone acetyl transferase that is also regulated by phosphorylation on and H. L. R. K. K. 2000; PubMed Scopus Google Scholar). be that the the ATF2 and other involved in the control of transcription factors, and and the amino acid regulation of gene expression. In to ATF2 and other transcription factors that belong to the ATF or C/EBP families have the to bind in the AARE and C/EBPβ bind the AARE sequence and the transcriptional However, it is not that a in the amino acid control of the CHOP transcription. and C/EBPβ are to activate transcription of of the AARE that are not to leucine starvation. C/EBPβ does not the amino acid regulation of CHOP expression A. Averous J. Zhong C. Kilberg M.S. Fafournoux P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google and the of does not CHOP induction by leucine starvation. However, that these transcription factors belong to the protein binds the AARE sequence and the response to amino acid starvation. is that transcription factors that belong to the C/EBP or ATF families are to bind the AARE of several transcription factors and bind the AARE sequence to control the of transcription. show that ATF2 and ATF4 are involved in the amino acid regulation of CHOP transcription. these two H. A. K. Cell PubMed Scopus Google have that ATF2 and ATF4 may a that binds the AARE be in a protein it has been shown that ATF2 with at least two factors and in a protein that transcription of the gene J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We have also shown the pathway that to ATF4 other amino acid-dependent are to ATF2 and to activate the AARE-dependent transcription. The of these and their with the pathway to be the of molecular by the concentration of amino acid gene expression be to our understanding of control in mammalian We S. C. and A. for of the and for We K. New and P. of for with