Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-κB in Response to Diverse Cellular Stresses

Jiang, Hao; Wek, Sheree A.; McGrath, Barbara C.; Scheuner, Donalyn; Kaufman, Randal J.; Cavener, Douglas R.; Wek, Ronald C.

doi:10.1128/mcb.23.16.5651-5663.2003

Cited by 389 publications

(356 citation statements)

References 77 publications

Supporting

Mentioning

330

Contrasting

Unclassified

Order By: Relevance

“…ative PKR was overexpressed in PERKϪ/Ϫ fibroblasts, there was no rescue of cyclin D1 protein levels; the kinetics of cyclin D1 loss matched those of cells transfected with empty vector. Consistent with our results, the activation of additional eIF2␣ kinases during the UPR has been reported previously (Jiang et al, 2003(Jiang et al, , 2004.…”

Section: Cyclin D1 Loss Requires Phosphorylation Of Eif2␣supporting

confidence: 82%

“…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%

“…We reasoned that in the absence of PERK, another eIF2␣ kinase might function redundantly to promote eIF2␣ phosphorylation and resultant inhibition of protein synthesis during ER stress, as demonstrated by recent data (Jiang et al, 2003(Jiang et al, , 2004. Wild-type or PERKϪ/Ϫ fibroblasts were treated with tunicamycin for the indicated intervals, or left untreated.…”

Section: Molecular Biology Of the Cell 5494mentioning

confidence: 99%

See 2 more Smart Citations

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

228

176

View full text Add to dashboard Cite

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...

show abstract

Section: Cyclin D1 Loss Requires Phosphorylation Of Eif2␣supporting

confidence: 82%

Section: Functional Cooperativity Among Eif2␣ Kinasessupporting

confidence: 82%

Section: Molecular Biology Of the Cell 5494mentioning

confidence: 99%

See 1 more Smart Citation

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

228

176

View full text Add to dashboard Cite

show abstract

“…A recent finding that the eIF2a phosphorylation is required for induction of NFkB suggests that the stresstransducing molecule for EOR is shared with other ER stressinduced transcriptional program. 15 The fourth is apoptosis, which occurs when functions of the ER are severely impaired, to protect the organism by eliminating the damaged cells. 16,17 At least three apoptosis pathways are known to be involved in this apoptotic event.…”

mentioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

show abstract

“…and dysregulate the sterol regulatory element binding proteins (SREBPs), transcription factors that control lipid biosynthesis and uptake [62,73,74]. ER stress-inducing agents have been shown to promote the activation of NF-κB, the transcription factor that is responsible for promoting the expression of genes involved in inflammatory processes [75]. Finally, ER stress has been shown to induce the activation of caspases and promote apoptosis of human aortic endothelial cells and hepatocytes [62,76].…”

Section: O-glcnacasementioning

confidence: 99%

Molecular and Cellular Mechanisms by Which Diabetes Mellitus Promotes the Development of Atherosclerosis

Werstuck

Biochemistry of Atherosclerosis

View full text Add to dashboard Cite

Recent decades have witnessed a significant increase in the incidence of diabetes mellitus primarily driven by population trends toward weight gain and sedentary lifestyles. Diabetes mellitus is a leading cause of blindness, renal failure, lower limb amputation, and an independent risk factor for atherosclerotic cardiovascular disease (CVD) and stroke. In fact, individuals with diabetes have a two-to fourfold increased risk of myocardial infarction (MI) and stroke that accounts for over 65% of diabetic mortality. Despite a vast amount of research, the molecular and cellular mechanisms that predispose individuals with diabetes to the development and progression of atherosclerosis are not understood. This chapter summarizes the current state of our knowledge of these conditions as well as some of the animal models that are being used to further increase our understanding. In addition, pathways and mechanisms that may link diabetes, and hyperglycemia in particular, to the development and progression of atherosclerosis are discussed. The continued investigation of identified pathways, linking hyperglycemia and diabetes mellitus to atherosclerosis, and the discovery of novel mechanisms and targets will be important to the development of new and effective antiatherosclerotic therapies tailored to individuals with diabetes.

show abstract

Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-κB in Response to Diverse Cellular Stresses

Cited by 389 publications

References 77 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

Roles of CHOP/GADD153 in endoplasmic reticulum stress

Molecular and Cellular Mechanisms by Which Diabetes Mellitus Promotes the Development of Atherosclerosis

Contact Info

Product

Resources

About