MEK Signaling Is Required for Phosphorylation of eIF2α following Amino Acid Limitation of HepG2 Human Hepatoma Cells

The mammalian amino acid response (AAR) pathway is up-regulated by protein or amino acid depletion. This pathway involves detection of uncharged tRNA by the GCN2 kinase, phosphorylation of the translation initiation factor eIF2α (eukaryotic initiation factor 2α), and, through subsequent translational control, enhanced de novo synthesis of the transcription factor ATF4. The present studies demonstrate that inhibition of MEK activation in HepG2 human hepatoma cells by PD98059 or U0126 blocked the increased phosphorylation of eIF2α and ATF4 synthesis triggered by amino acid limitation, showing that the AAR requires activation of the MEK-ERK pathway. Inhibitors of the JNK or p38 MAPK pathways were ineffective. Consequently, inhibition of MEK activation blocked transcriptional induction of ATF4 target genes, but the induction was rescued by overexpression of ATF4 protein. Furthermore, the enhanced ERK phosphorylation following amino acid deprivation required GCN2 kinase activity and eIF2α phosphorylation. Inhibition of protein phosphatase 1 action on phospho-eIF2α by knockdown of GADD34 did not block the sensitivity to PD98059, suggesting that MEK functions to enhance GCN2-dependent eIF2α phosphorylation rather than suppressing dephosphorylation. Collectively, these results document a critical interdependence between the MEK-ERK MAPK signaling pathway and the amino acid stress-activated pathway. The mammalian amino acid response (AAR) pathway is up-regulated by protein or amino acid depletion. This pathway involves detection of uncharged tRNA by the GCN2 kinase, phosphorylation of the translation initiation factor eIF2α (eukaryotic initiation factor 2α), and, through subsequent translational control, enhanced de novo synthesis of the transcription factor ATF4. The present studies demonstrate that inhibition of MEK activation in HepG2 human hepatoma cells by PD98059 or U0126 blocked the increased phosphorylation of eIF2α and ATF4 synthesis triggered by amino acid limitation, showing that the AAR requires activation of the MEK-ERK pathway. Inhibitors of the JNK or p38 MAPK pathways were ineffective. Consequently, inhibition of MEK activation blocked transcriptional induction of ATF4 target genes, but the induction was rescued by overexpression of ATF4 protein. Furthermore, the enhanced ERK phosphorylation following amino acid deprivation required GCN2 kinase activity and eIF2α phosphorylation. Inhibition of protein phosphatase 1 action on phospho-eIF2α by knockdown of GADD34 did not block the sensitivity to PD98059, suggesting that MEK functions to enhance GCN2-dependent eIF2α phosphorylation rather than suppressing dephosphorylation. Collectively, these results document a critical interdependence between the MEK-ERK MAPK signaling pathway and the amino acid stress-activated pathway. Activation of the mammalian amino acid response (AAR) 4The abbreviations used are: AAR, amino acid response; AARE, amino acid response element; p-eIF2α, eIF2α phosphorylated at Ser-51; ERK, extracellular signal-regulated kinase; p-ERK, phosphorylated ERK; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; PP1, protein phosphatase 1; uORF, upstream open reading frame; MEM, minimal essential medium; DMEM, Dulbecco's modified Eagle's medium; MEF, mouse embryo fibroblast; siRNA, short interfering RNA. pathway occurs in response to protein and/or amino acid deprivation in vivo (1Straus D.S. Burke E.J. Marten N.W. Endocrinology. 1993; 132: 1090-1100Crossref PubMed Scopus (82) Google Scholar, 2Endo Y. Fu Z. Abe K. Arai S. Kato H. J. Nutr. 2002; 132: 3632-3637Crossref PubMed Scopus (82) Google Scholar, 3Hao S. Sharp J.W. Ross-Inta C.M. McDaniel B.J. Anthony T.G. Wek R.C. Cavener D.R. McGrath B.C. Rudell J.B. Koehnle T.J. Gietzen D.W. Science. 2005; 307: 1776-1778Crossref PubMed Scopus (267) Google Scholar, 4Maurin A.C. Jousse C. Averous J. Parry L. Bruhat A. Cherasse Y. Zeng H. Zhang Y. Harding H.P. Ron D. Fafournoux P. Cell Metab. 2005; 1: 273-277Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar) as well as to amino acid limitation in vitro (reviewed in Ref. 5Kilberg M.S. Pan Y.X. Chen H. Leung-Pineda V. Annu. Rev. Nutr. 2005; 25: 59-85Crossref PubMed Scopus (221) Google Scholar). Without an adequate supply of essential amino acids, the binding of uncharged tRNA activates the GCN2 (general control nondeprepressible-2) kinase, which in turn, phosphorylates serine 51 of the α subunit of the translation initiation factor eIF2 (eukaryotic initiation factor 2) (6Hinnebusch A.G. J. Biol. Chem. 1997; 272: 21661-21664Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). The Ser-51-phosphorylated eIF2α (p-eIF2α) functions as an inhibitor of eIF2B, which is responsible for the GDP-GTP exchange that regulates eIF2 activity; therefore, the resulting elevated level of p-eIF2α suppresses global translation initiation (6Hinnebusch A.G. J. Biol. Chem. 1997; 272: 21661-21664Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). Dephosphorylation of Ser-51 p-eIF2α is mediated by protein phosphatase 1 (PP1), which is targeted to p-eIF2α by interaction with the growth arrest and DNA damage gene GADD34 (7Novoa I. Zeng H. Harding H.P. Ron D. J. Cell Biol. 2001; 153: 1011-1021Crossref PubMed Scopus (1049) Google Scholar, 8Brush M.H. Weiser D.C. Shenolikar S. Mol. Cell. Biol. 2003; 23: 1292-1303Crossref PubMed Scopus (299) Google Scholar). The PP1-GADD34 action on p-eIF2α is proposed to be a component of the program of recovery from the translational inhibition to allow for synthesis of stress-responsive proteins (9Novoa I. Zhang Y. Zeng H. Jungreis R. Harding H.P. Ron D. EMBO J. 2003; 22: 1180-1187Crossref PubMed Scopus (356) Google Scholar). Although eIF2α phosphorylation leads to a suppression of general protein synthesis, paradoxically, there is an increase in the synthesis of ATF4 (activating transcription factor 4) from preexisting mRNA through a mechanism based on ribosome scanning and reinitiation efficiency involving upstream open reading frames (uORFs) within the ATF4 mRNA (10Vattem K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1147) Google Scholar, 11Lu P.D. Harding H.P. Ron D. J. Cell Biol. 2004; 167: 27-33Crossref PubMed Scopus (667) Google Scholar). Elevated ATF4 protein results in the activation of a wide array of stress-induced genes (12Harding 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 (2410) Google Scholar), including those that contain an amino acid response element (AARE) (5Kilberg M.S. Pan Y.X. Chen H. Leung-Pineda V. Annu. Rev. Nutr. 2005; 25: 59-85Crossref PubMed Scopus (221) Google Scholar). Among the ATF4-responsive, AARE-containing genes is SNAT2 (System A neutral amino acid transporter) (13Palii S.S. Chen H. Kilberg M.S. J. Biol. Chem. 2004; 279: 3463-3471Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 14Palii S.S. Thiaville M.M. Pan Y.X. Zhong C. Kilberg M.S. Biochem. J. 2006; 395: 517-527Crossref PubMed Scopus (62) Google Scholar, 15Gaccioli F. Huang C.C. Wang C. Bevilacqua E. R. M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). and to the activation of protein kinase as the mitogen-activated protein kinase mammalian there MAPK the extracellular signal-regulated kinase the c-Jun N-terminal kinase and the p38 The ERK pathway involves the activation of protein MAPK/ERK kinase and ERK Mol. Cell. Biol. PubMed Scopus Google Scholar). acid to activity by at by protein phosphatase D. K. M. M. N. H. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. P. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The enhanced kinase activity the signaling which in in an amino a protein that regulates the of by protein D. K. M. M. N. H. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. S. J. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). A between the pathway and the transcription signaling not well and the of the present was to for a between the ERK and eIF2α phosphorylation. M.M. T.J. J. 2006; PubMed Scopus Google Scholar) that from cells in that a ERK which of eIF2α by the action of and, in general protein The of that that of translation for the of to a wide of on the or the enhanced of functions following amino acid deprivation to be on or of the MAPK R. R. V. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that amino acid the increase in A activity was blocked by the MEK activation inhibitor the of those the genes that A activity were not the for MEK action in the induction of A activity was not was that the SNAT2 gene the amino A activity R. R. V. V. 2001; PubMed Scopus Google Scholar, R. Chen H. S.S. K.M. Kilberg M.S. J. Nutr. 2002; 132: PubMed Scopus Google Scholar), and that the SNAT2 gene an within the (13Palii S.S. Chen H. Kilberg M.S. J. Biol. Chem. 2004; 279: 3463-3471Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 14Palii S.S. Thiaville M.M. Pan Y.X. Zhong C. Kilberg M.S. Biochem. J. 2006; 395: 517-527Crossref PubMed Scopus (62) Google Scholar). Consequently, induction of SNAT2 in response to amino acid limitation is on eIF2α phosphorylation and the subsequent synthesis of ATF4 F. Huang C.C. Wang C. Bevilacqua E. R. M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). present in HepG2 human hepatoma demonstrate an between activation of the pathway and eIF2α phosphorylation The results document following amino acid MEK and ERK as by increased ERK and activation required GCN2 kinase that MEK the phosphorylation of eIF2α on Ser-51 by GCN2 and the subsequent of the transcription factor ATF4 was to be on Inhibition of eIF2α phosphatase activity by GADD34 arrest and DNA gene did not the sensitivity to MEK that MEK functions to enhance GCN2-dependent eIF2α phosphorylation rather than to the with a for enhanced MEK activity within the AAR the of transcriptional signaling to MEK be rescued by of ATF4. the that MEK is by a GCN2-dependent and that there is an for signaling upstream of translational control in the mammalian AAR pathway. Inhibitors and and the following were from MEK inhibitor p38 inhibitor MEK inhibitor PD98059, and JNK inhibitor to ATF4 ERK and were from to eIF2α and p-eIF2α at Ser-51 were from Cell Cell human hepatoma cells were in modified Eagle's minimal essential with amino acids, and and at in an of and from and GCN2 that by were by Harding and Ron H.P. Novoa I. Zhang Y. Zeng H. Wek R. M. Ron D. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). cells from the eIF2α or a the that D. B. E. C. R. P. T. S. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The cells were in Dulbecco's modified Eagle's with with amino acids, and B. to cells were and to that deprivation to the of amino acid deprivation in the of kinase PD98059 U0126 or cells were with the inhibitor in for 1 and with the inhibitor in or mRNA mRNA was the with to of DNA the or GADD34 was the DNA and were at for by for and of at for and for that a was the were for by a increase of the from to and were at were to that there was DNA The used for ATF4 mRNA were as The used for GADD34 mRNA were as The used to SNAT2 mRNA or to transcription activity from the SNAT2 gene by were S.S. Thiaville M.M. Pan Y.X. Zhong C. Kilberg M.S. Biochem. J. 2006; 395: 517-527Crossref PubMed Scopus (62) Google Scholar). The used to mRNA were as the were as and and protein were in and protein was a modified M.S. PubMed Scopus Google Scholar). of was and were with to and blocked with and for 1 at was used at a between and in and with at or for at The were for in and with the at a to for 1 at The were for in and in and The was an enhanced and the to DNA were as V. Kilberg M.S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). DNA at a of 1 a DNA an was used to a of and of HepG2 of was to the The was to with and phosphatase V. Kilberg M.S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) and for 1 at The were for with in of and for to the protein. A was and to the and cells were in at a of and for to S.S. Thiaville M.M. Pan Y.X. Zhong C. Kilberg M.S. Biochem. J. 2006; 395: 517-527Crossref PubMed Scopus (62) Google Scholar), was used to cells with 1 of the AARE-containing SNAT2 to or in with of the for ATF4 by the The ATF4 the upstream open reading that the mRNA to translational Consequently, the ATF4 protein is from DNA was at by to the were for for and for in MEM, PD98059, or were the for was used to between The as the of at the of MEK activity on ATF4 translation HepG2 cells were the with 1 of a or a and by the of Ron Wek (10Vattem K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1147) Google Scholar). were with of an as a were in control or with or PD98059 for and and were the or not MEK or ERK eIF2α phosphorylation on human cells were S.S. Thiaville M.M. Pan Y.X. Zhong C. Kilberg M.S. Biochem. J. 2006; 395: 517-527Crossref PubMed Scopus (62) Google Scholar), with the for a MEK, or a eIF2α the serine 51 phosphorylation were for eIF2α p-eIF2α, or human and were from HepG2 cells were in at a of in and for was to the of of and a well HepG2 cells were with for and with MEM, and for The was and with control or with or and protein were at and by or Inhibition of MEK Activation the of an AARE-containing and the in of ATF4 to an R. R. V. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that the increased A amino acid activity that occurs following amino acid deprivation is blocked by inhibition of MEK activation the inhibitor amino A activity was to from increased transcription from the SNAT2 gene R. R. V. V. 2001; PubMed Scopus Google Scholar, R. Chen H. S.S. K.M. Kilberg M.S. J. Nutr. 2002; 132: PubMed Scopus Google Scholar). that deprivation of HepG2 cells increased which is blocked by PD98059 V. Pan Y. Chen H. Kilberg M.S. Biochem. J. 2004; PubMed Scopus Google Scholar). with these HepG2 cells were for in the of PD98059 the increase in SNAT2 mRNA was blocked of PD98059 was for transcriptional induction of amino not The induction of transcription from these AARE-containing genes following amino acid limitation with the increase in ATF4 protein H. Pan Y.X. Kilberg M.S. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, overexpression of ATF4 transcription from a and by in vivo and in vitro that ATF4 to the within of the SNAT2 gene S.S. Thiaville M.M. Pan Y.X. Zhong C. Kilberg M.S. Biochem. J. 2006; 395: 517-527Crossref PubMed Scopus (62) Google Scholar). Consequently, the of MEK inhibition on ATF4 binding activity was A DNA was an AARE-containing DNA that was with from HepG2 cells that for in or The of ATF4 binding activity was in the from amino cells with those from control cells the cells were with the MEK the increase in ATF4 binding activity was The of Inhibitors on ATF4 mRNA and to enhanced ATF4 there is an increase in ATF4 mRNA following amino acid deprivation F. R. Chen H. Kilberg M.S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). to the of MEK activity on ATF4 mRNA and protein HepG2 cells were with PD98059 as well as with for p38 or JNK The p38 and JNK did not the induction of ATF4 mRNA JNK activity elevated the of ATF4 mRNA the inhibitor of PD98059, the increase in ATF4 transcription from the ATF4 gene is the of ATF4 protein following amino acid deprivation is enhanced translation of preexisting ATF4 mRNA (10Vattem K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1147) Google Scholar, 11Lu P.D. Harding H.P. Ron D. J. Cell Biol. 2004; 167: 27-33Crossref PubMed Scopus (667) Google Scholar), the increase in ATF4 protein was in the of the MAPK The p38 inhibitor on the amino acid increase in ATF4 protein but inhibition of MEK blocked the inhibition of JNK an enhanced ATF4 in the novo synthesis results in a increase in HepG2 ATF4 protein of deprivation and a of H. Pan Y.X. Kilberg M.S. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). that the MAPK pathway in was at a of a of ATF4 synthesis with or PD98059 was the ATF4 of control cells increased at with a level by the cells with PD98059 a block of ATF4 protein at the translation of preexisting ATF4 mRNA is enhanced following amino acid limitation, increased phosphorylation of eIF2α translation initiation at the ATF4 rather than at an (10Vattem K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1147) Google Scholar, 11Lu P.D. Harding H.P. Ron D. J. Cell Biol. 2004; 167: 27-33Crossref PubMed Scopus (667) Google Scholar). the translation of ATF4 was blocked by inhibition of MEK cells were with an the ATF4 or within the as to the translation (10Vattem K.M. Wek R.C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11269-11274Crossref PubMed Scopus (1147) Google Scholar). the translation of the was enhanced and synthesis was blocked by PD98059 of the that translation was in but ATF4 synthesis and of an by The of a on activity not and on the ATF4 synthesis that PD98059 not global MEK kinase activity is required for the transcriptional and the translational that to increased ATF4 following amino acid ATF4 the Inhibition of by MEK is that inhibition of MEK is SNAT2 transcription of on ATF4 protein MEK inhibition PD98059 inhibition of SNAT2 transcription be rescued by of ATF4 protein. a gene by an AARE-containing SNAT2 was HepG2 cells with an ATF4 The ATF4 the upstream open reading within the mRNA that of ATF4 the cells were in amino acid or with or the of the MEK activation inhibitor the of the SNAT2 mediated an increase in activity of amino acid limitation, and the of increase was blocked cells were with PD98059 to the for the SNAT2 gene in the was with an for ATF4 ATF4 transcription was to but the of the MEK inhibitor or demonstrate that the of transcriptional activation following inhibition of MEK activity be rescued by ATF4. of MEK Inhibition on of that PD98059 blocked of ATF4 was that MEK activity is required for the AAR pathway upstream of eIF2α phosphorylation. Cell from HepG2 cells for in or with or PD98059, were for eIF2α or p-eIF2α amino acid limitation, there was an increase in the phosphorylation of eIF2α at that a level of between and the MEK activation was phosphorylation of eIF2α was these were for MEK, studies were in the of a inhibitor of MEK which in a in the stress-induced phosphorylation of eIF2α and the subsequent synthesis of ATF4 document that ATF4 mRNA translation requires the action of MEK at a upstream of eIF2α phosphorylation. MEK ERK to eIF2α on MEK or target ERK to the of phosphorylation of eIF2α on a of MEK was in cells a control, eIF2α or a eIF2α serine 51 was for that overexpression of MEK activation of the were for the phosphorylation of the of MEK but not of GCN2 MEK ERK phosphorylates eIF2α on The not the that MEK, ERK, or a of ERK phosphorylates eIF2α at a than with these of the eIF2α protein not MAPK kinase eIF2α or the eIF2α acid limitation activates the eIF2α kinase but as of a a phosphatase mediated by a of protein phosphatase 1 and GADD34 is as the of de novo GADD34 synthesis (7Novoa I. Zeng H. Harding H.P. Ron D. J. Cell Biol. 2001; 153: 1011-1021Crossref PubMed Scopus (1049) Google Scholar, I. Zhang Y. Zeng H. Jungreis R. Harding H.P. Ron D. EMBO J. 2003; 22: 1180-1187Crossref PubMed Scopus (356) Google Scholar). The phosphatase is targeted to p-eIF2α of the with GADD34 M.H. Weiser D.C. Shenolikar S. Mol. Cell. Biol. 2003; 23: 1292-1303Crossref PubMed Scopus (299) Google Scholar). was that the of enhanced eIF2α phosphorylation on was to inhibition of the PP1-GADD34 by GADD34 transcription or by the phosphatase the the of of MEK activation on GADD34 mRNA was to an increase in GADD34 mRNA deprivation an increase in GADD34 but induction was MEK activation was with the of MEK for ATF4 synthesis, that ATF4 is responsible for the induction of the GADD34 the results that not to enhance eIF2α phosphorylation by GADD34 an increase in GADD34 mRNA PD98059 or not MEK p-eIF2α by the activity of the PP1-GADD34 HepG2 cells were with an and the AAR pathway was at including phosphorylation of eIF2α ATF4 and SNAT2 transcription a control, these with The of the increase in GADD34 mRNA following amino acid limitation was and the of MEK activation GADD34 of GADD34 the level of p-eIF2α but the increased eIF2α phosphorylation ATF4 synthesis and SNAT2 transcription were activation of the AAR the of GADD34 in Furthermore, in the of inhibition of MEK the AAR pathway. Activation of the on GCN2 and the that the of in eIF2α phosphorylation is to or enhance the phosphorylation rather than through inhibition of dephosphorylation. or not the AAR pathway is the mechanism by which signaling is is or not or was an amino mRNA was but mRNA was increased not with the of in ERK protein that the increased following amino acid deprivation was upstream of ATF4 Consequently, cells were used to the activation of ERK was on GCN2 or eIF2α phosphorylation. were with from GCN2 or an eIF2α that of serine at 51 The cells were to deprivation for and ERK phosphorylation and ATF4 were increased ATF4 synthesis did not in cells GCN2 or the deprivation in the increase in in the GCN2 and increased phosphorylation of ERK was not in the cells for GCN2 Although the level of was in the cells the of and to ERK there was increase in the level of phosphorylation amino acid The results from the to demonstrate that phosphorylation of eIF2α by the amino kinase GCN2 requires MEK a the de novo synthesis of ATF4 and subsequent transcription program is on activation of the signaling MAPK pathway. was that amino acid deprivation activates MEK as by ERK phosphorylation. The results that the of MEK action is to and/or enhance eIF2α not dephosphorylation. as in the an interdependence between stress-activated pathways within the the following The activation of signaling by amino acid limitation was on GCN2 and phosphorylation of 2) the MAPK pathways the pathway was essential for activation of signaling in HepG2 activation of the AAR by amino acid limitation, enhanced phosphorylation of eIF2α was on MEK 4) with the between MEK activity and eIF2α the stress-induced increase in ATF4 protein and DNA binding activity was on increased MEK that transcription was on MEK activity and that inhibition of transcription be rescued by of ATF4. of GADD34 did not the of eIF2α phosphorylation on MEK, a action on the PP1-GADD34 Although that than GCN2 to amino acid limitation, the present studies involving cells that the activation of occurs of and is on GCN2 MAPK signaling to be A of studies that amino acid limitation increased ERK phosphorylation. R. R. V. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that of amino an increase in ERK phosphorylation. and S. C. P. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, E. S. J. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that cells in amino by a Sharp J.W. Ross-Inta C.M. S. Rudell J.B. Gietzen D.W. J. 2006; PubMed Scopus Google Scholar) that elevated of ERK and eIF2α in a of which were to be in amino of the for the amino acid as in the present an increase in ERK which was for a increase in V. Pan Y. Chen H. Kilberg M.S. Biochem. J. 2004; PubMed Scopus Google Scholar). there is showing a between the pathway and eIF2α but in that in the was to that in the present an level of ERK and inhibition of that activity by the MEK inhibitor U0126 an increase in the phosphorylation of eIF2α a involving suppression of inhibition of activity M.M. T.J. J. 2006; PubMed Scopus Google Scholar). the HepG2 hepatoma cells inhibition of the pathway blocked the eIF2α suggesting that the between the MEK and eIF2α pathways be M.M. T.J. J. 2006; PubMed Scopus Google Scholar) that JNK which in turn, leads to an increase in phosphorylated eIF2α (7Novoa I. Zeng H. Harding H.P. Ron D. J. Cell Biol. 2001; 153: 1011-1021Crossref PubMed Scopus (1049) Google Scholar, I. Zhang Y. Zeng H. Jungreis R. Harding H.P. Ron D. EMBO J. 2003; 22: 1180-1187Crossref PubMed Scopus (356) Google Scholar). is with the present showing that inhibition of JNK an increase in ATF4 in amino This that in the HepG2 hepatoma cells and the JNK the of eIF2α phosphorylation by inhibition of phosphorylation of eIF2α is the of a between or of the stress-induced eIF2 GCN2 and the of dephosphorylation. is that these pathways the synthesis of GADD34 (7Novoa I. Zeng H. Harding H.P. Ron D. J. Cell Biol. 2001; 153: 1011-1021Crossref PubMed Scopus (1049) Google Scholar, I. Zhang Y. Zeng H. Jungreis R. Harding H.P. Ron D. EMBO J. 2003; 22: 1180-1187Crossref PubMed Scopus (356) Google Scholar) and that GADD34 is responsible for the to the and eIF2α M.H. Weiser D.C. Shenolikar S. Mol. Cell. Biol. 2003; 23: 1292-1303Crossref PubMed Scopus (299) Google Scholar). The present document that the increase in eIF2α phosphorylation amino acid deprivation is on MEK activation in cells with GADD34 This that the pathway to enhance the phosphorylation of eIF2α by GCN2 rather than suppressing the dephosphorylation. the phosphorylation of GCN2 with and PD98059 not be by or of the of the were to the action of MEK is upstream or of of cells for a amino acid a response that the pathways with that amino deprivation of for results in of of genes not amino acid but genes in and K. D. C. A.G. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). of mouse a wide of genes (12Harding 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 (2410) Google Scholar). mammalian eIF2α M. Annu. Rev. Biochem. 2005; PubMed Scopus Google Scholar), and and Ron and (12Harding 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 (2410) Google Scholar, H.P. Calfon M. F. Novoa I. Ron D. Annu. Rev. Cell Biol. 2002; PubMed Scopus Google Scholar) to the which the of stress-activated on Although the present document that the MAPK pathway MEK is for the GCN2 eIF2α kinase, is that or of the MAPK pathways be required for action by eIF2α with was in T. F. Zhang Y. Z. Scopus Google Scholar) showing that leads to phosphorylation of eIF2α in an Zhang McGrath B.C. Zhang P. Cavener D.R. Biochem. J. 2006; PubMed Scopus Google Scholar) that but not a activation of the JNK and p38 studies to which array of through eIF2α on of the MAPK of the Kilberg for and the from Ron Wek the MEK by of the eIF2α and by and the GCN2 and cells from Harding and Ron

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