Regulatory proteins of eukaryotic initiation factor 2‐alpha subunit (eIF2α) phosphatase, under ischemic reperfusion and tolerance

García-Bonilla, Lidia; Cid, Cristina; Alcázar, Alberto; Bürda, Jozef; Ayuso, María Irene; Salinas, Matilde

doi:10.1111/j.1471-4159.2007.04844.x

Cited by 24 publications

(20 citation statements)

References 75 publications

(204 reference statements)

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“…The samples were homogenized 1:5 (w/v) with buffer A (20 m m Tris-HCl, pH 7.5; 140 m m potassium chloride; 5 m m magnesium acetate; 1 m m dithiothreitol; 2 m m benzamidine; 1 m m EDTA; 2 m m EGTA; 10 μg/ml pepstatin A, leupeptin, and antipain; 20 m m sodium β-glycerophosphate; 20 m m sodium molybdate; 0.2 m m sodium orthovanadate), as described previously (16, 18). The homogenate was centrifuged at 11,000 × g for 15 min to obtain a postmitochondrial supernatant (PMS).…”

Section: Methodsmentioning

confidence: 99%

New Hierarchical Phosphorylation Pathway of the Translational Repressor eIF4E-binding Protein 1 (4E-BP1) in Ischemia-Reperfusion Stress

Ayuso

Hernández-Jiménez

Martı́n³

et al. 2010

Journal of Biological Chemistry

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Eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) is a translational repressor that is characterized by its capacity to bind specifically to eIF4E and inhibit its interaction with eIF4G. Phosphorylation of 4E-BP1 regulates eIF4E availability, and therefore, cap-dependent translation, in cell stress. This study reports a physiological study of 4E-BP1 regulation by phosphorylation using control conditions and a stress-induced translational repression condition, ischemia-reperfusion (IR) stress, in brain tissue. In control conditions, 4E-BP1 was found in four phosphorylation states that were detected by two-dimensional gel electrophoresis and Western blotting, which corresponded to Thr69-phosphorylated alone, Thr69- and Thr36/Thr45-phosphorylated, all these plus Ser64 phosphorylation, and dephosphorylation of the sites analyzed. In control or IR conditions, no Thr36/Thr45 phosphorylation alone was detected without Thr69 phosphorylation, and neither was Ser64 phosphorylation without Thr36/Thr45/Thr69 phosphorylation detected. Ischemic stress induced 4E-BP1 dephosphorylation at Thr69, Thr36/Thr45, and Ser64 residues, with 4E-BP1 remaining phosphorylated at Thr69 alone or dephosphorylated. In the subsequent reperfusion, 4E-BP1 phosphorylation was induced at Thr36/Thr45 and Ser64, in addition to Thr69. Changes in 4E-BP1 phosphorylation after IR were according to those found for Akt and mammalian target of rapamycin (mTOR) kinases. These results demonstrate a new hierarchical phosphorylation for 4E-BP1 regulation in which Thr69 is phosphorylated first followed by Thr36/Thr45 phosphorylation, and Ser64 is phosphorylated last. Thr69 phosphorylation alone allows binding to eIF4E, and subsequent Thr36/Thr45 phosphorylation was sufficient to dissociate 4E-BP1 from eIF4E, which led to eIF4E-4G interaction. These data help to elucidate the physiological role of 4E-BP1 phosphorylation in controlling protein synthesis.

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Section: Methodsmentioning

confidence: 99%

New Hierarchical Phosphorylation Pathway of the Translational Repressor eIF4E-binding Protein 1 (4E-BP1) in Ischemia-Reperfusion Stress

Ayuso

Hernández-Jiménez

Martı́n³

et al. 2010

Journal of Biological Chemistry

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“…GRP78 was only detected in PP1γ immunoprecipitates. Thus, we suggest that PP1 through different signaling complexes with their interacting proteins, modulates the phosphorylation states of eIF2α, and affects tolerance acquisition with the important role of GADD34/PP1c complexes (García‐Bonilla et al,2007).…”

Section: Translational Machinery and Antioxidant Defensementioning

confidence: 98%

Ischemic Tolerance: The Mechanisms of Neuroprotective Strategy

Lehotský

Bürda

Danielisová³

et al. 2009

The Anatomical Record

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The phenomenon of ischemic tolerance perfectly describes this quote ''What does not kill you makes you stronger.'' Ischemic pre-or postconditioning is actually the strongest known procedure to prevent or reverse neurodegeneration. It works specifically in sensitive vulnerable neuronal populations, which are represented by pyramidal neurons in the hippocampal CA1 region. However, tolerance is effective in other brain cell populations as well. Although, its nomenclature is ''ischemic'' tolerance, the tolerant phenotype can also be induced by other stimuli that lead to delayed neuronal death (intoxication). Moreover, the recent data have proven that this phenomenon is not limited to application of sublethal stimuli before the lethal stress but reversed arrangement of events, sublethal stress after lethal insult, is rather equally effective. A very important term is called ''cross conditioning.'' Cross conditioning is the capability of one stressor to induce tolerance against another. So, since pre-or postconditioners can be used plenty of harmful stimuli, hypo-or hyperthermia and some physiological compounds, such as norepinephrine, bradykinin. Delayed neuronal death is the slow development of postischemic neurodegeneration. This allows an opportunity for a great therapeutic window of 2-3 days to reverse the cellular death process. Moreover, it seems that the mechanisms of ischemic tolerance-delayed postconditioning could be used not only after ischemia but also in some other processes leading to apoptosis.

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“…PP1 contributes to cellular recovery from stress by acting as an eIF2␣ phosphatase. PP1 regulators inhibitor-1 (I-1), growth arrest and DNA damageinducible protein 34 (GADD34), and constitutive repressor of eIF2␣ phosphorylation (CReP) target PP1c to eIF2␣ to dephosphorylate it (29). In the setting of stress, kinases other than PKR are known to phosphorylate eIF2␣ (30 -32).…”

Section: Respiratory Syncytial Virus (Rsv)mentioning

confidence: 99%

Respiratory Syncytial Virus Limits α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation to Maintain Translation and Viral Replication

Groskreutz¹,

Babor²,

Monick³

et al. 2010

Journal of Biological Chemistry

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The impact of respiratory syncytial virus (RSV) on morbidity and mortality is significant in that it causes bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and pneumonia in immunocompromised hosts. RSV activates protein kinase R (PKR) Respiratory syncytial virus (RSV) 2 is a ubiquitous pathogen that causes upper respiratory infections in healthy adults, bronchiolitis and pneumonia in young children, exacerbations in patients with obstructive lung disease, and life-threatening pneumonia in immunosuppressed patients. RSV infection early in life has been associated with the subsequent development of asthma (2-9). RSV is a member of the Paramyxoviridae family and consists of a negative strand RNA genome in a nucleocapsid surrounded by an envelope (10). Production of dsRNA is part of the replicative cycle for RNA viruses like RSV, and RNA serves as a template for both transcription and replication (11). Entry into the host respiratory epithelium is by cell surface fusion, and infection leads to viral replication and subsequent host inflammatory responses (12-17).,We previously showed that RSV increases the amount of protein kinase R (PKR) in airway epithelial cells (1). When activated by phosphorylation, PKR inhibits cellular translation through its ability to phosphorylate eIF2␣ on the Ser-51 regulatory site (18). eIF2␣ is a GTP-binding protein that delivers the initiator methionyl-tRNA to the small ribosomal subunit in translation initiation. Phosphorylation of eIF2␣ converts eIF2 from a substrate to an inhibitor of its GDP-GTP exchange factor eIF2B, blocking protein synthesis (19). If the phosphorylation of PKR during RSV infection triggers activation of eIF2␣, then cellular and viral protein translation should markedly decrease. However, viral protein translation occurs in a robust fashion during RSV infection.Viruses have different strategies to maintain viral protein translation, and PKR plays a limited role with some viruses and cell types. Subgenomic hepatitis C virus RNA replicates more efficiently in PKR knock-out mouse embryonic fibroblasts than in wild type mouse embryonic fibroblasts. The suppression of PKR activity by small interfering RNA enhances the level of hepatitis C virus RNA replication, suggesting PKR controls hepatitis C virus replication, likely via eIF2␣ phosphorylation (20). These findings were confirmed in PKR knockdown cells (21). However, inhibition of PKR by antisense peptide-conjugated phosphorodiamidate morpholino oligomers has no effect on severe acute respiratory syndrome virus titers nor does it affect the severe acute respiratory syndrome-induced phosphorylation of eIF2␣ (22). These observations suggest that another eIF2␣ kinase may regulate its activation or the severe acute respiratory syndrome virus has direct inhibitory effects on eIF2␣. Additionally, cells void of PKR protein by RNA interference do not alter the growth of adenovirus, reovirus, or measles virus (22,23). Studies using alphavirus demonstrate a decrease in viral titers in PKR Ϫ/...

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Regulatory proteins of eukaryotic initiation factor 2‐alpha subunit (eIF2α) phosphatase, under ischemic reperfusion and tolerance

Cited by 24 publications

References 75 publications

New Hierarchical Phosphorylation Pathway of the Translational Repressor eIF4E-binding Protein 1 (4E-BP1) in Ischemia-Reperfusion Stress

New Hierarchical Phosphorylation Pathway of the Translational Repressor eIF4E-binding Protein 1 (4E-BP1) in Ischemia-Reperfusion Stress

Ischemic Tolerance: The Mechanisms of Neuroprotective Strategy

Respiratory Syncytial Virus Limits α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation to Maintain Translation and Viral Replication

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