Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein: Implications for eIF2α-Dependent Gene Expression and Cell Death

Kazemi, Shirin; Papadopoulou, S.; Li, Suiyang; Su, Qiaozhu; Wang, Shuo; Yoshimura, Akihiko; Matlashewski, Greg; Dever, Thomas E.; Koromilas, Antonis E.

doi:10.1128/mcb.24.8.3415-3429.2004

Cited by 92 publications

(103 citation statements)

References 81 publications

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“…To verify the ability of PKR to mediate JNK activation, we used human HT1080 cells expressing a conditionally active from of PKR, which is activated after treatment of cells with the antibiotic coumermycin. 6 We found that conditional activation of PKR, which was assessed by the eIF2a phosphorylation, led to JNK1 activation by phosphorylation as detected by immunoblotting with phospho-specific antibodies (Supplementary Figure S3). Taken together, these findings showed the ability of PKR to induce JNK activity in mouse and human cells in response to doxorubicin.…”

Section: Resultsmentioning

confidence: 99%

“…4,5 However, prolonged induction of eIF2a phosphorylation is mainly proapoptotic. 5,6 Although eIF2a phosphorylation has a major role in mediating the biological effects of the eIF2a kinases, their ability to function independently of eIF2a phosphorylation has been reported. 7,8 Received 21.12.09; revised 19.5.10; accepted 19.5.10; Edited by RA Knight; published online 18.6.10 These authors contributed equally to this work.…”

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confidence: 99%

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Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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The eukaryotic cell responds to various forms of environmental stress by adjusting the rates of mRNA translation thus facilitating adaptation to the assaulting stress. One of the major pathways that control protein synthesis involves the phosphorylation of the a-subunit of eukaryotic initiation factor eIF2 at serine 51. Different forms of DNA damage were shown to induce eIF2a phosphorylation by using PERK, GCN2 or PKR. However, the specificity of the eIF2a kinases and the biological role of eIF2a phosphorylation pathway in the DNA damage response (DDR) induced by chemotherapeutics are not known. Herein, we show that PKR is the eIF2a kinase that responds to DDR induced by doxorubicin. We show that activation of PKR integrates two signaling pathways with opposing biological outcomes. More specifically, induction of eIF2a phosphorylation has a cytoprotective role, whereas activation of c-jun N-terminal kinase (JNK) by PKR promotes cell death in response to doxorubicin. We further show that the proapoptotic effects of JNK activation prevail over the cytoprotection mediated by eIF2a phosphorylation. These findings reveal that PKR can be an important inducer of cell death in response to chemotherapies through its ability to act independently of eIF2a phosphorylation. The eukaryotic cell has established intricate mechanisms to cope with environmental stress. It does so by changing protein expression in a manner that promotes adaptation to the assaulting stress. Protein expression within the cell is regulated at the transcriptional, translational and posttranslational levels. Translational control is often used under conditions of cellular stress because it allows immediate and selective changes in protein levels. 1 Translation itself is divided into three distinct phases: initiation, elongation and termination. By far the most explored step is that of initiation, which has been shown to be regulated by different extracellular stimuli. 1 One of the major pathways that control translation initiation is that of the phosphorylation of the a-subunit of translation initiation factor eIF2. 2 Phosphorylation of eIF2a at serine 51 (S51) leads to the inhibition of global protein synthesis providing the cell with the opportunity to elicit adaptive responses not only by saving energy but also by preventing the accumulation of unwanted proteins that could interfere with cellular functions. 1 There are four eIF2a kinases that share a homologous kinase domain (KD) but possess different regulatory domains that enable them to become activated by distinct stimuli. 2 The eIF2a kinases are the heme-regulated inhibitor, which is found mainly in erythroid cells and is activated by heme deficiency; the endoplasmic reticulum (ER)-resident kinase (PERK), which is activated by ER stress and inhibits protein synthesis as part of the unfolded protein response; the general aminoacid nonderepressing kinase 2 (GCN2), which responds to amino-acid deprivation and becomes activated by uncharged tRNA and the RNA-dependent protein kinase PKR, an interfer...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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“…For example, PKR signals through STAT1 and STAT3 (36,43,44), interferon regulatory factor 1 (IRF1) (16,45), IRF3 (46), p53 (17,47,48), and the IKK complex to regulate transcription during proinflammatory (16,17,40,45) and/or proapoptotic responses (12,40,45,49). PKR-dependent apoptosis was also associated with Fas-associated death domain (FADD)-mediated activation of caspase 8 (50,51) and up-regulation of Fas and Bax (18,52,53). In addition, PKR can signal through the mitogen-activated protein kinase cascade to activate p38 and JNK in the innate immune response to bacterial endotoxin (54).…”

Section: Discussionmentioning

confidence: 99%

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

Scheuner

Patel

Wang

et al. 2006

Journal of Biological Chemistry

122

100

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As the molecular processes of complex cell stress signaling pathways are defined, the subsequent challenge is to elucidate how each individual event influences the final biological outcome. Phosphorylation of the translation initiation factor 2 (eIF2␣) at Ser 51 is a molecular signal that inhibits translation in response to activation of any of four diverse eIF2␣ stress kinases. We used gene targeting to replace the wild-type Ser 51 allele with an Ala in the eIF2␣ gene to test the hypothesis that translational control through eIF2␣ phosphorylation is a central death stimulus in eukaryotic cells. Homozygous eIF2␣ mutant mouse embryo fibroblasts were resistant to the apoptotic effects of dsRNA, tumor necrosis factor-␣, and serum deprivation. TNF␣ treatment induced eIF2␣ phosphorylation and activation of caspase 3 primarily through the dsRNA-activated eIF2␣ kinase PKR. In addition, expression of a phospho-mimetic Ser 51 to Asp mutant eIF2␣-activated caspase 3, indicating that eIF2␣ phosphorylation is sufficient to induce apoptosis. The proapoptotic effects of PKR-mediated eIF2␣ phosphorylation contrast with the anti-apoptotic response upon activation of the PKR-related endoplasmic reticulum eIF2␣ kinase, PERK. Therefore, divergent fates of death and survival can be mediated through phosphorylation at the same site within eIF2␣. We propose that eIF2␣ phosphorylation is fundamentally a death signal, yet it may promote either death or survival, depending upon coincident signaling events.

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“…Cell Culture and Treatments-HT1080 cells expressing GyrB.PKR wild type (WT) were established as described (32). HT1080 parental and GyrB.PKR WT cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% calf serum (Invitrogen) and 100 units/ml of penicillin-streptomycin (Wisent).…”

Section: Methodsmentioning

confidence: 99%

“…HT1080 cells stably expressing a chimeric protein in which the catalytic domain of PKR was fused to the first 220 amino acids of the Escherichia coli gyrase B protein were analyzed (32). Treatment of these cells with the antibiotic coumermycin caused dimerization of the GyrB domain and autophosphorylation and activation of PKR (32).…”

Section: Down-regulation Of Cyclin D1 Requires Eif2␣mentioning

confidence: 99%

PKR and PKR-like Endoplasmic Reticulum Kinase Induce the Proteasome-dependent Degradation of Cyclin D1 via a Mechanism Requiring Eukaryotic Initiation Factor 2α Phosphorylation

Raven

Baltzis

Wang

et al. 2008

Journal of Biological Chemistry

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Cyclin D1 plays a critical role in controlling the G 1 /S transition via the regulation of cyclin-dependent kinase activity. Several studies have indicated that cyclin D1 translation is decreased upon activation of the eukaryotic initiation factor 2␣ (eIF2␣) kinases. We examined the effect of activation of the eIF2␣ kinases PKR and PKR-like endoplasmic reticulum kinase (PERK) on cyclin D1 protein levels and translation and determined that cyclin D1 protein levels decrease upon the induction of PKR and PERK catalytic activity but that this decrease is not due to translation. Inhibition of the 26 S proteasome with MG132 rescued cyclin D1 protein levels, indicating that rather than inhibiting translation, PKR and PERK act to increase cyclin D1 degradation. Interestingly, this effect still requires eIF2␣ phosphorylation at serine 51, as cyclin D1 remains unaffected in cells containing a non-phosphorylatable form of the protein. This proteasome-dependent degradation of cyclin D1 requires an intact ubiquitination pathway, although the ubiquitination of cyclin D1 is not itself affected. Furthermore, this degradation is independent of phosphorylation of cyclin D1 at threonine 286, which is mediated by the glycogen synthase kinase 3␤ and mitogen-activated protein kinase pathways as described in previous studies. Our study reveals a novel functional cross-talk between eIF2␣ phosphorylation and the proteasomal degradation of cyclin D1 and that this degradation is dependent upon eIF2␣ phosphorylation during short, but not prolonged, periods of stress.

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Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein: Implications for eIF2α-Dependent Gene Expression and Cell Death

Cited by 92 publications

References 81 publications

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

PKR and PKR-like Endoplasmic Reticulum Kinase Induce the Proteasome-dependent Degradation of Cyclin D1 via a Mechanism Requiring Eukaryotic Initiation Factor 2α Phosphorylation

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