Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response

Jiang, Hao; Wek, Sheree A.; McGrath, Barbara C.; Lü, Dan; Hai, Tsonwin; Harding, Heather P.; Wang, Xiaozhong; Ron, David; Cavener, Douglas R.; Wek, Ronald C.

doi:10.1128/mcb.24.3.1365-1377.2004

Cited by 454 publications

(451 citation statements)

References 78 publications

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“…Whole cell lysates (see above) were subject to immunoblot analysis using a phosphospecific antibody to serine 51 of eIF2␣. In agreement with previous data ( Figure 2C; Jiang et al, 2003Jiang et al, , 2004, eIF2␣ is phosphorylated in PERKϪ/Ϫ fibroblasts with delayed kinetics ( Figure 5B, top, lanes 5-10) in comparison with wild-type cells (lanes 1-5). However, eIF2␣ phosphorylation is completely abrogated in PERK/ GCN2Ϫ/Ϫ fibroblasts ( Figure 5B, top, lanes 11-15).…”

Section: Functional Cooperativity Among Eif2␣ Kinasessupporting

confidence: 82%

“…Of the four known eIF2␣ kinases, GCN2 and PKR are the most likely to serve in this capacity because expression of the fourth eIF2␣ kinase, HRI, is restricted to erythroid cells. We assessed cyclin D1 protein synthesis in fibroblasts isolated from mice lacking PERK, GCN2, and PKR (TKO cells) (Jiang et al, 2004). Wild-type or TKO cells were treated with 0.5 g/ml tunicamycin for 12 h or left untreated.…”

Section: Functional Cooperativity Among Eif2␣ Kinasesmentioning

confidence: 99%

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PERK and GCN2 Contribute to eIF2α Phosphorylation and Cell Cycle Arrest after Activation of the Unfolded Protein Response Pathway

Hamanaka

Bennett

Cullinan

et al. 2005

MBoC

231

180

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Exposure of cells to endoplasmic reticulum (ER) stress leads to activation of PKR-like ER kinase (PERK), eukaryotic translation initiation factor 2␣ (eIF2␣) phosphorylation, repression of cyclin D1 translation, and subsequent cell cycle arrest in G 1 phase. However, whether PERK is solely responsible for regulating cyclin D1 accumulation after unfolded protein response pathway (UPR) activation has not been assessed. Herein, we demonstrate that repression of cyclin D1 translation after UPR activation occurs independently of PERK, but it remains dependent on eIF2␣ phosphorylation. Although phosphorylation of eIF2␣ in PERK؊/؊ fibroblasts is attenuated in comparison with wild-type fibroblasts, it is not eliminated. The residual eIF2␣ phosphorylation correlates with the kinetics of cyclin D1 loss, suggesting that another eIF2␣ kinase functions in the absence of PERK. In cells harboring targeted deletion of both PERK and GCN2, cyclin D1 loss is attenuated, suggesting GCN2 functions as the redundant kinase. Consistent with these results, cyclin D1 translation is also stabilized in cells expressing a nonphosphorylatable allele of eIF2␣; in contrast, repression of global protein translation still occurs in these cells, highlighting a high degree of specificity in transcripts targeted for translation inhibition by phosphorylated eIF2␣. Our results demonstrate that PERK and GCN2 function to cooperatively regulate eIF2␣ phosphorylation and cyclin D1 translation after UPR activation. INTRODUCTIONIntegral membrane proteins and secreted proteins are synthesized, folded, and posttranslationally modified in the endoplasmic reticulum (ER). When the integrity of protein folding in the ER is compromised and misfolded proteins accumulate, a signaling network referred to as the unfolded protein response pathway (UPR) is activated (Kaufman, 1999). Stresses that activate the UPR include disruption of proper protein glycosylation (glucose deprivation or treatment of cells with drugs that directly inhibit glycosylation such as tunicamycin), perturbations in ER calcium homeostasis (thapsigargin), perturbations in ER redox status (dithiothreitol [DTT]), and hypoxia (Kaufman, 1999;Koumenis et al., 2002).Activation of the UPR triggers a checkpoint that provides cells with the opportunity to adapt and survive, or under conditions of chronic stress, to commit to a program of cell death. The proximal effectors of the mammalian UPR include the three homologous, ER-resident transmembrane protein kinases Ire1 (␣ and ␤) and PKR-like ER kinase (PERK); the ER-resident transmembrane protease caspase 12; and the ER-resident transmembrane bZIP transcription factor ATF6 (Cox et al., 1993;Shi et al., 1998;Tirasophon et al., 1998;Wang et al., 1998;Harding et al., 1999;Haze et al., 1999;Nakagawa et al., 2000). Ire1 and PERK both have luminal, ER stress-sensing domains that regulate their dimerization and activation of their protein kinase activity. Activation of ATF6 occurs via a proteolytic cleavage that allows its translocation to the nucleus where it fun...

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Section: Functional Cooperativity Among Eif2␣ Kinasessupporting

confidence: 82%

Section: Functional Cooperativity Among Eif2␣ Kinasesmentioning

confidence: 99%

PERK and GCN2 Contribute to eIF2α Phosphorylation and Cell Cycle Arrest after Activation of the Unfolded Protein Response Pathway

Hamanaka

Bennett

Cullinan

et al. 2005

MBoC

231

180

View full text Add to dashboard Cite

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“…Gene expression profiling of PDT-treated cancer cells E Buytaert et al UPR activation was further evidenced by the concurrent upregulation of XBP1 (X-box-binding protein 1), a transcription factor regulating various UPR-target genes including ER-resident chaperones (Schroder and Kaufman, 2005). Interestingly, ATF3, a highly PDTinduced stress gene ( Figure 1b, Table 1) encoding a member of the ATF/cAMP-responsive element binding protein family of transcription factors, has been reported to be a PERK target (Jiang et al, 2004), suggesting a link between ATF3 induction and ER stress in our paradigm. PDT also upregulated TRIB3, a downstream negative modulator of the CHOP/ATF4 pathway (Ohoka et al, 2005), the ER protein HER-PUD1 which is involved in ER-associated degradation (ERAD), and SERP1, an ER translocon complex protein (Ma and Hendershot, 2004;Hori et al, 2006).…”

Section: Global Distribution Of Hypericin-pdt Differentially Expressementioning

confidence: 99%

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

et al. 2007

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Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O 2 , cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38 MAPK inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38 MAPK inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer.

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“…118 At least in some contexts, this may be mediated by upregulation of GADD34 mRNA by CHOP 116 and/or the transcription factor ATF3, which is also upregulated by ATF4. 120 Therefore, the regulation of eIF2a by GADD34/PP1 completes a feedback loop to control translation: during ER stress, PERK phosphorylates eIF2a, which induces the expression of ATF4, ATF3 and CHOP. These transcription factors then upregulate GADD34, which mediates the dephosphorylation of eIF2a by PP1.…”

Section: Esr In Mammalsmentioning

confidence: 99%

Cellular response to endoplasmic reticulum stress: a matter of life or death

2006

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The proper functioning of the endoplasmic reticulum (ER) is critical for numerous aspects of cell physiology. Accordingly, all eukaryotes react rapidly to ER dysfunction through a set of adaptive pathways known collectively as the ER stress response (ESR). Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger programmed cell death, or apoptosis. ER stress and the apoptotic program coupled to it have been implicated in many important pathologies but the regulation and execution of ER stressinduced apoptosis in mammals remain incompletely understood. Here, we review what is known about the ESR in both yeast and mammals, and highlight recent findings on the mechanism and pathophysiological importance of ER stressinduced apoptosis.

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Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response

Cited by 454 publications

References 78 publications

PERK and GCN2 Contribute to eIF2α Phosphorylation and Cell Cycle Arrest after Activation of the Unfolded Protein Response Pathway

PERK and GCN2 Contribute to eIF2α Phosphorylation and Cell Cycle Arrest after Activation of the Unfolded Protein Response Pathway

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

Cellular response to endoplasmic reticulum stress: a matter of life or death

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