Phosphorylation of eIF2 Directs ATF5 Translational Control in Response to Diverse Stress Conditions

Phosphorylation of eukaryotic initiation factor 2 (eIF2) is an important mechanism regulating global and gene-specific translation in response to different environmental stresses. Central to the eIF2 kinase response is the preferential translation of ATF4 mRNA, encoding a transcriptional activator of genes involved in stress remediation. In this report, we addressed whether there are additional transcription factors whose translational expression is regulated by eIF2 kinases. We show that the expression of the basic zipper transcriptional regulator ATF5 is induced in response to many different stresses, including endoplasmic reticulum stress, arsenite exposure, and proteasome inhibition, by a mechanism requiring eIF2 phosphorylation. ATF5 is subject to translational control as illustrated by the preferential association of ATF5 mRNA with large polyribosomes in response to stress. ATF5 translational control involves two upstream open reading frames (uORFs) located in the 5′-leader of the ATF5 mRNA, a feature shared with ATF4. Mutational analyses of the 5′-leader of ATF5 mRNA fused to a luciferase reporter suggest that the 5′-proximal uORF1 is positive-acting, allowing scanning ribosomes to reinitiate translation of a downstream ORF. During non-stressed conditions, when eIF2 phosphorylation is low, ribosomes reinitiate translation at the next ORF, the inhibitory uORF2. Phosphorylation of eIF2 during stress delays translation reinitiation, allowing scanning ribosomes to bypass uORF2, and instead translate the ATF5 coding region. In addition to translational control, ATF5 mRNA levels are significantly reduced in ATF4-/- mouse embryo fibroblasts, suggesting that ATF4 contributes to basal ATF5 transcription. These results demonstrate that eIF2 kinases direct the translational expression of multiple transcription regulators by a mechanism involving delayed translation reinitiation. Phosphorylation of eukaryotic initiation factor 2 (eIF2) is an important mechanism regulating global and gene-specific translation in response to different environmental stresses. Central to the eIF2 kinase response is the preferential translation of ATF4 mRNA, encoding a transcriptional activator of genes involved in stress remediation. In this report, we addressed whether there are additional transcription factors whose translational expression is regulated by eIF2 kinases. We show that the expression of the basic zipper transcriptional regulator ATF5 is induced in response to many different stresses, including endoplasmic reticulum stress, arsenite exposure, and proteasome inhibition, by a mechanism requiring eIF2 phosphorylation. ATF5 is subject to translational control as illustrated by the preferential association of ATF5 mRNA with large polyribosomes in response to stress. ATF5 translational control involves two upstream open reading frames (uORFs) located in the 5′-leader of the ATF5 mRNA, a feature shared with ATF4. Mutational analyses of the 5′-leader of ATF5 mRNA fused to a luciferase reporter suggest that the 5′-proximal uORF1 is positive-acting, allowing scanning ribosomes to reinitiate translation of a downstream ORF. During non-stressed conditions, when eIF2 phosphorylation is low, ribosomes reinitiate translation at the next ORF, the inhibitory uORF2. Phosphorylation of eIF2 during stress delays translation reinitiation, allowing scanning ribosomes to bypass uORF2, and instead translate the ATF5 coding region. In addition to translational control, ATF5 mRNA levels are significantly reduced in ATF4-/- mouse embryo fibroblasts, suggesting that ATF4 contributes to basal ATF5 transcription. These results demonstrate that eIF2 kinases direct the translational expression of multiple transcription regulators by a mechanism involving delayed translation reinitiation. Phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2) 2The abbreviations used are:eIF2eukaryotic initiation factor 2ERendoplasmic reticulumbZIPbasic zipperORFopen reading frameuORFupstream open reading frameMEFmouse embryonic fibroblastRTreverse transcriptionRACErapid amplification of cDNA ends.2The abbreviations used are:eIF2eukaryotic initiation factor 2ERendoplasmic reticulumbZIPbasic zipperORFopen reading frameuORFupstream open reading frameMEFmouse embryonic fibroblastRTreverse transcriptionRACErapid amplification of cDNA ends. is an important mechanism regulating protein synthesis in response to a diverse range of environmental stresses (1Dever T.E. Cell. 2002; 108: 545-556Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, 2Holcik M. Sonenberg N. Nat. Rev. Mol. Cell. Biol. 2005; 6: 318-327Crossref PubMed Scopus (1029) Google Scholar, 3Wek R.C. Jiang H.Y. Anthony T.G. Biochem. Soc. Trans. 2006; 34: 7-11Crossref PubMed Scopus (1013) Google Scholar). Four eIF2α kinases have been described in mammals, each responding to different stress arrangements through their unique regulatory regions. For example, phosphorylation of eIF2α by PEK (also known as Perk or EIF2AK3) is induced by accumulation of malfolded proteins in the endoplasmic reticulum (ER) (4Ron D. Walter P. Nat. Rev. Mol. Cell. Biol. 2007; 8: 519-529Crossref PubMed Scopus (4851) Google Scholar, 5Marciniak S.J. Ron D. Physiol. Rev. 2006; 86: 1133-1149Crossref PubMed Scopus (777) Google Scholar, 6Schroder M. Kaufman R.J. Annu. Rev. Biochem. 2005; 74: 739-789Crossref PubMed Scopus (2432) Google Scholar). Phosphorylation of eIF2α during this so-called ER stress inhibits global translation by lowering the levels of eIF2-GTP that are central for binding of initiator Met-tRNAiMet to the translational machinery (1Dever T.E. Cell. 2002; 108: 545-556Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, 2Holcik M. Sonenberg N. Nat. Rev. Mol. Cell. Biol. 2005; 6: 318-327Crossref PubMed Scopus (1029) Google Scholar, 3Wek R.C. Jiang H.Y. Anthony T.G. Biochem. Soc. Trans. 2006; 34: 7-11Crossref PubMed Scopus (1013) Google Scholar). Together with reduced protein synthesis, eIF2α phosphorylation increases the preferential translation of ATF4 mRNA, encoding a basic zipper (bZIP) transcription activator that is important for directing the expression of genes involved in metabolism, the redox status of cells, and apoptosis (7Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2364) Google Scholar, 8Vattem K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1122) Google Scholar, 9Lu P.D. Harding H.P. Ron D. J. Cell Biol. 2004; 167: 27-33Crossref PubMed Scopus (654) Google Scholar). Decreased protein synthesis conserves energy and provides sufficient time for ATF4, and other stress-responsive transcription factors, to reconfigure gene expression that would block or ameliorate damage elicited by the underlying stress. Other members of the eIF2α kinase whose is by or proteasome is regulated by and and in an M. Sonenberg N. Nat. Rev. Mol. Cell. Biol. 2005; 6: 318-327Crossref PubMed Scopus (1029) Google Scholar, 3Wek R.C. Jiang H.Y. Anthony T.G. Biochem. Soc. Trans. 2006; 34: 7-11Crossref PubMed Scopus (1013) Google Scholar, 6Schroder M. Kaufman R.J. Annu. Rev. Biochem. 2005; 74: 739-789Crossref PubMed Scopus (2432) Google Scholar, R.C. 2007; PubMed Scopus Google Scholar). in eIF2α kinase are with a of including and eukaryotic initiation factor 2 endoplasmic reticulum basic zipper open reading upstream open reading mouse embryonic transcription amplification of cDNA ends. eukaryotic initiation factor 2 endoplasmic reticulum basic zipper open reading upstream open reading mouse embryonic transcription amplification of cDNA ends. ATF4 expression during eIF2α phosphorylation by translational control, as illustrated by association of ATF4 mRNA with H.P. Novoa I. Zhang Y. Zeng H. Wek R. M. Ron D. Mol. Cell. 6: Full Text Full Text PDF PubMed Scopus Google Scholar). Central to ATF4 translational control is the 5′-leader of the ATF4 mRNA, two that have K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1122) Google Scholar, 9Lu P.D. Harding H.P. Ron D. J. Cell Biol. 2004; 167: 27-33Crossref PubMed Scopus (654) Google Scholar). ATF4 translation with the subunit to scanning the of the ATF4 mRNA and translation at the uORF1 ribosomes are to association with ATF4 mRNA and reinitiate translation at a downstream coding M. Sonenberg N. Nat. Rev. Mol. Cell. Biol. 2005; 6: 318-327Crossref PubMed Scopus (1029) Google Scholar, 8Vattem K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1122) Google Scholar, R.C. 2007; PubMed Scopus Google Scholar). In non-stressed when eIF2α phosphorylation is and there is ribosomes scanning downstream uORF1 reinitiate translation at the next ORF, the inhibitory uORF2. translation of uORF2, ribosomes are to the ATF4 to translation of the ATF4 coding region. During stress conditions, phosphorylation of eIF2α eIF2-GTP the time for scanning ribosomes to to reinitiate translation of delayed would for a of the ribosomes to bypass the initiation and instead translate the ATF4 coding region. central feature in ATF4 translational translation in response to eIF2α is shared with the mechanism that translation of a transcriptional regulator in Annu. Rev. 2005; PubMed Scopus Google Scholar). ATF4 or with other transcription factors, and ATF4 synthesis contributes to binding of this transcription activator to the of genes (4Ron D. Walter P. Nat. Rev. Mol. Cell. Biol. 2007; 8: 519-529Crossref PubMed Scopus (4851) Google Scholar, 6Schroder M. Kaufman R.J. Annu. Rev. Biochem. 2005; 74: 739-789Crossref PubMed Scopus (2432) Google Scholar, C. M. A. M. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, H. Annu. Rev. 2005; PubMed Scopus Google Scholar). genes is a transcriptional regulator that apoptosis during stress S.J. Ron D. Physiol. Rev. 2006; 86: 1133-1149Crossref PubMed Scopus (777) Google Scholar, 6Schroder M. Kaufman R.J. Annu. Rev. Biochem. 2005; 74: 739-789Crossref PubMed Scopus (2432) Google Scholar, H. M. N. H. Ron D. PubMed Scopus Google Scholar, S.J. Yun S. Novoa I. Zhang Y. R. Harding H.P. Ron D. 2004; PubMed Scopus Google Scholar). ATF4 and to the transcriptional expression of encoding a subunit for a protein that eIF2α S.J. Ron D. Physiol. Rev. 2006; 86: 1133-1149Crossref PubMed Scopus (777) Google Scholar, S.J. Yun S. Novoa I. Zhang Y. R. Harding H.P. Ron D. 2004; PubMed Scopus Google Scholar). the is important for directing control of the eIF2α kinase allowing for translation of induced ATF4. and ATF4-/- mouse embryo that of the genes requiring eIF2α phosphorylation for their in response to ER stress, ATF4 (7Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2364) Google Scholar). These results suggest that there additional transcription factors that are important for directing the eIF2α kinase and are subject to translational We the central for transcription in the eIF2α kinase there additional proteins that are subject to translational control in response to eIF2α phosphorylation. is a transcriptional regulator that is by an mRNA that two with to that described in the ATF4 C. M. A. M. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, C. K.M. T.E. K.M. 2002; PubMed Scopus Google Scholar). ATF5 mRNA is in many different with the levels in C. K.M. T.E. K.M. 2002; PubMed Scopus Google Scholar). ATF5 is to a in and reduced ATF5 by to to of cells, as J.M. P.D. J. M. A. 2005; Scopus Google Scholar). ATF5 is to in cells, and is in expression of ATF5 is to for J.M. P.D. J. M. A. 2005; Scopus Google Scholar, J.M. J. 2005; PubMed Scopus Google Scholar, J.M. C. J. 2003; PubMed Google Scholar, J.M. Mol. Cell 2005; PubMed Scopus Google Scholar). In this we that expression of ATF5 protein is induced in response to eIF2α phosphorylation during a range of different stress ATF5 expression by a translational mechanism involving and located in the 5′-leader of the ATF5 with this translational control, we that ATF5 mRNA levels are significantly reduced in ATF4-/- cells, suggesting a for transcription of results suggest that eIF2α phosphorylation ATF5 and this transcription factor is to the eIF2α kinase of ATF5 and ATF5 cDNA the and of that an of ATF5 an and in and at with in with an of and to the and at for by in and and a in the and of the by and by with of ATF5 protein to in the to with and at with and the ATF5 protein with ATF5 protein and by the ATF5 by and the ATF5 protein the and ATF5 ATF5 described in the the ATF5 protein and ATF5 in mouse and that induced by different stress Cell and that and described D. B. C. R. P. T. S. Kaufman R.J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, H.Y. Wek D. R.J. Wek R.C. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). and cells, and their H.Y. Wek Lu D. T. Harding H.P. Ron D. Wek R.C. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). in with and ER stress elicited in by the addition of or to the by for to as arsenite or of the proteasome to the and the for to as block to cells, as as described H. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google and with arsenite or of and and in or non-stressed two with and in a with of and of and for Cell by and protein by the protein for the of each protein by and proteins to of known to the of proteins in the in and with by with with that the ATF5 ATF5 as described ATF4 an ATF4. and that eIF2α at that or of eIF2α by of in and the and in the are of and analyses as described T. Biochem. PubMed Scopus Google Scholar). and with or stress, for the of the the of each by a and by and and to for the and by of mRNA in and with the with for or stress. to the luciferase reporter gene used in a to and used to a encoding the ATF5 mRNA and ATF5 initiation and in a of the of the ATF5 coding fused to the luciferase reporter gene downstream of a initiation in each of the in the ATF5 mRNA or in to the the to that there the the and to and the in or of the and a luciferase as an control with for or with ER stress. luciferase as described by the are a of a of luciferase and the of are as that used to the of ATF5 to the of the in with or stress, a amplification of cDNA the there amplification of to the of ATF5 with this ER stress or stress. of with in the of other with to the a that to a that in the transcription and to the of ATF5 as as to the by the of the two to ATF5 mRNA the and used for the of with the described of the by and the by and the and transcriptional as the that to the that to of the of ATF5 in as in the of or to stress, for to the to and in with and with and through a for of cells, for and by at for at a and for 2 at in a the and the of at by an a of each as described by the and the ATF4 ATF4 ATF5 ATF5 and For of mRNA of cDNA each with for and to the range of In this used for for ATF4, and for ATF5 and the with Phosphorylation of eIF2α for ATF5 in to ATF5 mRNA two that are many different including and 5′-proximal uORF1 a that is in that is the different ATF5 downstream a in in and to in the ATF5 In each example, the of with the ATF5 coding the of in ATF4 translational control in response to eIF2α we addressed whether the levels of ATF5 protein in response to environmental stresses by a mechanism requiring eIF2α phosphorylation. cells, and a for the phosphorylation in to different stress known to eIF2α phosphorylation and downstream ATF4. stress involved of with a ER stress that the eIF2α kinase PEK M. Kaufman R.J. Annu. Rev. Biochem. 2005; 74: 739-789Crossref PubMed Scopus (2432) Google Scholar, R.C. 2007; PubMed Scopus Google Scholar). stress that elicited by arsenite to multiple eIF2α of eIF2α kinase gene in block phosphorylation of stress involved with a of proteasome that phosphorylation of eIF2α in H.Y. Wek R.C. J. Biol. 2005; Scholar). of stress the eIF2α kinase in cells, with eIF2α phosphorylation and ATF4 protein levels of in the there phosphorylation of eIF2α and ATF4 there ATF5 protein levels in in response to each of the stress exposure, ATF5 expression induced with levels of this transcriptional activator of the of ER stress and increases in ATF5 levels of ATF5 protein of the stress and ATF5 protein in the cells, are of eIF2α in response to each of the stress These central to other and to that have been for of the eIF2α H. Annu. Rev. 2005; PubMed Scopus Google Scholar, H.Y. Wek Lu D. T. Harding H.P. Ron D. Wek R.C. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar, C. C. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). cells, and to for to ATF5 expression in the of ER stress, with eIF2α phosphorylation and levels of ATF4, and gene in the cells, there ATF5 with reduced eIF2α phosphorylation and downstream ATF4 and In response to of eIF2α phosphorylation and induced ATF5 the of the eIF2α kinase for ATF5 levels in response to proteasome have been to a eIF2α kinase stress response during different stress H. Annu. Rev. 2005; PubMed Scopus Google Scholar, H. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). We the with or arsenite for to and that ATF5 levels in a time to that of ATF4 in response to stress of the ATF4 of each stress. These results that ATF5 expression is induced by a diverse range of environmental stresses by a mechanism requiring eIF2α phosphorylation. ATF5 expression during the different stress arrangements in and and in different Phosphorylation of eIF2α and ATF4 for of eIF2α kinase translational and transcriptional expression in response to stress. whether ATF5 mRNA levels in response to stress, we analyses and with or increases in ATF4 mRNA levels in with or arsenite for to and ATF4 mRNA in ATF4-/- that with stress the of the in the In ATF4 mRNA levels in the with or arsenite and levels of ATF4 in the of eIF2α phosphorylation transcription or of the ATF4 mRNA that These suggest that of ATF4 expression during stress the translational control and in mRNA ATF4 to the transcription in response to different stresses H. Annu. Rev. 2005; PubMed Scopus Google Scholar, J. A. C. P. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Biochem. J. PubMed Scopus Google Scholar). with this that mRNA levels are significantly in response to with or arsenite expression in the ATF4-/- cells, or the cells, levels of ATF4 levels of ATF5 mRNA in in response to there an in the of ATF5 mRNA of arsenite stress, ATF5 in non-stressed there a in the of ATF5 mRNA in the ATF4-/- and cells, including levels in the basal conditions, and stress These results suggest that the eIF2α kinase the transcriptional activator ATF4, is for ATF5 mRNA levels in the basal and eIF2α kinase genes are regulated by translational and transcriptional control ATF5 is a for an the important of ATF4 in ATF5 mRNA and the that ATF5 protein is in the environmental stress, the of ATF5 of ATF5 by next to the of in the of ATF5 expression in response to stress. of ATF5 protein levels and ATF4-/- to arsenite stress that induced ATF5 expression ATF4 ATF5 protein of of arsenite exposure, there ATF5 protein in the ATF4-/- for ATF4 to that for been to ATF4 transcriptional in response to different stress conditions, including arsenite and (7Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2364) Google Scholar, H.P. Novoa I. Zhang Y. Zeng H. Wek R. M. Ron D. Mol. Cell. 6: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Biochem. J. PubMed Scopus Google Scholar, Y. J. Mol. Biol. 2002; PubMed Scopus Google Scholar). to the of transcriptional of control, we the with a known of to arsenite stress. ATF5 protein levels in response to the and arsenite the that significantly to induced ATF5 expression in response to environmental stress is that ATF5 levels reduced in the and arsenite with arsenite suggesting that transcriptional are a to ATF5 an additional of the ATF5 protein in the suggesting that ATF5 subject to as protein phosphorylation of ATF5 in with arsenite as as when with D. there ATF5 protein in the to that this to ATF5 expression uORF1 and of ATF5 the of translational control in ATF5 expression in response to stress, we a luciferase reporter that the ATF5 mRNA and initiation that upstream of a luciferase reporter gene that this of the ATF5 mRNA is mammals, we to the ATF5 for this reporter downstream of a kinase in the and transcriptional of the reporter gene by and and to to that of the ATF5 in 5′-leader is in and the two the ATF5 coding region. in response to ER stress, with the ATF5 transcription initiation in the reporter or in the and with for or stress. a in in the in response to the of in the during ER stress. of the mRNA in levels in the and These results the that ATF5 expression is subject to translational control by a mechanism involving the 5′-leader of the ATF5 mRNA and eIF2α as activator and as an in the mechanism regulating the ATF5 and different of the 5′-leader of the ATF5 mRNA fused to luciferase are to the of each luciferase the of and uORF2, and an a in the initiation of the and with the and a control luciferase with or stress as in the For the are in two different are levels of and of the reporter mRNA are in the and with the or of the reporter and to the mRNA levels for the reporter and with or stress as that uORF1 and in the 5′-leader of the reporter and that the reporter a in the initiation of the this reading for translational and that there in initiation of reading the of cells, and for the reporter in this In this the and the the of uORF1 and in the regulating ATF5 the for each to for translation reporter the uORF1 and or in the and and for expression in the or of ER stress. uORF1 in levels of in the or cells, of the 5′-proximal uORF1 as a in ATF5 translational the to an in in and cells, as with the of reporter uORF1 and is that this during or non-stressed levels of when the uORF1 and the reporter analyses of the different of mRNA in the and that in levels a to the in expression These results that as an inhibitory in ATF5 translational is is uORF1 for ATF5 expression We that uORF1 and have in the of ATF5 with uORF1 ribosomes to the inhibitory of uORF2. ATF5 mRNA in to reporter that ATF5 mRNA is in response to stress. this we the of mRNA association with ribosomes by In this is used to and polyribosomes Sonenberg N. Sonenberg N. Scholar, P. Scopus Google Scholar, J. Wek R.C. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). that are are to multiple or large that are to or In the non-stressed cells, mRNA to large polyribosomes ATF4 mRNA, is in the of stress, with ribosomes and ER stress, protein synthesis is reduced to PEK phosphorylation of eIF2-GTP levels to reduced and accumulation of in the stress to a in the ATF4 mRNA to the there lowering in the of ribosomes with of ATF5 mRNA in the a that that described for ATF4. In the non-stressed when protein synthesis is the ATF5 mRNA with as with the large with In response to ER stress, ATF5 mRNA in the with the that ATF5 mRNA to multiple ribosomes and These results the that translational control is an important underlying for ATF5 expression during environmental stress. Phosphorylation of eIF2α induced in response to diverse environmental stress translational and transcriptional regulatory to direct the expression of genes that or In this report, we that eIF2α phosphorylation is for expression of the transcriptional regulator ATF5 in response to each of different stress ER stress, arsenite exposure, and proteasome expression of ATF5 in response to stress involves two ATF5 is subject to translational expression of ATF5 protein in non-stressed conditions, the of ATF5 mRNA 2 and in response to stress conditions, and eIF2α there a in ATF5 protein levels In levels of ATF5 during stress in the of that transcription is for the ATF5 expression during stress ATF5 mRNA with large in response to ER stress, the that there is translation of ATF5 of an reporter that the 5′-leader of the ATF5 mRNA ATF5 translational underlying mechanism involves a uORF1 that ribosomes to bypass an inhibitory and of ATF5 translational control described for ATF4. regulatory mechanism with translation of for of ribosomes and at a downstream ORF. In non-stressed conditions, eIF2-GTP is allowing for scanning ribosomes to reinitiate translation at the next ORF, uORF2. translation of the inhibitory uORF2, ribosomes would downstream of the of the ATF5 coding and of ATF5 translation of uORF2, ribosomes the ATF5 translation of the inhibitory would to synthesis of the ATF5 transcription central feature of the in an inhibitory in ATF5 translational control, is in a by Y. N. M. H. N. H. S. Y. J. Biol. 2007; Full Text Full Text PDF PubMed Scopus Google that the of this In response to stress, the reduced levels of eIF2-GTP that during eIF2α phosphorylation reinitiation, allowing for scanning ribosomes to bypass the initiation scanning the the initiation of and the ATF5 coding would and translation at the ATF5 coding region. levels of ATF5 protein would to transcription of mechanism to ATF5 expression involves accumulation of ATF5 in cells, there in ATF5 levels to of ER stress, there in ATF5 mRNA levels during arsenite in mRNA levels during this stress to the synthesis of ATF5 in or in there a lowering in ATF5 mRNA and that ATF4, of eIF2α contributes or to ATF5 transcription. the of ATF4 for accumulation of ATF5 mRNA is during non-stressed conditions, suggesting that there is a basal of ATF4 protein that ATF5 mRNA ATF4-/- to to stress, requiring in the (7Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2364) Google Scholar). that ATF4 have in in the of with stress In this there stresses that increases in ATF4 These results suggest that translational control and ATF4 of ATF5 mRNA to ATF5 expression in response to different stress These of translational and transcriptional have been described for in as and R.C. J. J. in Scholar, C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, B. M. Mol. Biol. Cell. PubMed Scopus Google Scholar, C. S. H. S. J. 2002; PubMed Scopus Google Scholar). In each of synthesis of mRNA to important for expression of transcriptional expression of is to to translational control involving and translation that is delayed by eIF2α phosphorylation. is a the eIF2α kinase in Cell. 2002; PubMed Scopus Google this that have multiple transcriptional regulators subject to translational control in response to eIF2α phosphorylation. ATF5 have ATF5 mRNA the of ATF5 in and the of ATF5 in C. K.M. T.E. K.M. 2002; PubMed Scopus Google Scholar, J.M. P.D. J. M. A. 2005; Scopus Google Scholar, J.M. J. 2005; PubMed Scopus Google Scholar, J.M. C. J. 2003; PubMed Google Scholar, J.M. Mol. Cell 2005; PubMed Scopus Google Scholar). that ATF5 expression is induced by stress by requiring eIF2α phosphorylation to each of ATF5 two of ATF5 mRNA, to in and C. K.M. T.E. K.M. 2002; PubMed Scopus Google Scholar). in this to as mRNA, is during mouse and in with levels in and C. K.M. T.E. K.M. 2002; PubMed Scopus Google Scholar). that ATF5 is subject to translational control, ATF5 levels are an of ATF5 protein and of ATF5 mRNA, is at and to to mouse C. K.M. T.E. K.M. 2002; PubMed Scopus Google Scholar). an ATF5 coding with in the 5′-leader of the are in the each that described for the the the in is encoding a that with the ATF5 coding region. is to that this 5′-leader in the mRNA important of translational control as with the For example, the 5′-leader of mRNA the of scanning and the of translation reinitiation, the of translational control to eIF2α phosphorylation. We are to the of suggest that ATF5 is in cells, and ATF5 mRNA expression is a for and J.M. P.D. J. M. A. 2005; Scopus Google Scholar, J.M. J. 2005; PubMed Scopus Google Scholar, J.M. C. J. 2003; PubMed Google Scholar, J.M. Mol. Cell 2005; PubMed Scopus Google Scholar). this of ATF5 in in response to expression of a of ATF5 J.M. C. J. 2003; PubMed Google Scholar). In with the that ATF5 of and that ATF5 is in a of different J.M. P.D. J. M. A. 2005; Scopus Google Scholar). In the of ATF5 mRNA been to a in S. 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