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

Transient brain ischemia induces an inhibition of translational rates and causes delayed neuronal death in selective regions and cognitive deficits, whereas these effects do not occur in resistant areas. The translational repressor eukaryotic initiation factor (elF) 4E-binding protein-2 (4E-BP2) specifically binds to eIF4E and is critical in the control of protein synthesis. To link neuronal death to translation inhibition, we study the eIF4E association with 4E-BP2 under ischemia reperfusion in a rat model of transient forebrain ischemia. Upon reperfusion, a selective neuronal apoptosis in the hippocampal cornu ammonis 1 (CA1) region was induced, while it did not occur in the cerebral cortex. Confocal microscopy analysis showed a decrease in 4E-BP2/eIF4E colocalization in resistant cortical neurons after reperfusion. In contrast, in vulnerable CA1 neurons, 4E-BP2 remains associated to eIF4E with a higher degree of 4E-BP2/eIF4E colocalization and translation inhibition. Furthermore, the binding of a 4E-BP2 peptide to eIF4E induced neuronal apoptosis in the CA1 region. Finally, pharmacological-induced protection of CA1 neurons inhibited neuronal apoptosis, decreased 4E-BP2/eIF4E association, and recovered translation. These findings documented specific changes in 4E-BP2/eIF4E association during ischemic reperfusion, linking the translation inhibition to selective neuronal death, and identifying 4E-BP2 as a novel target for protection of vulnerable neurons in ischemic injury.

Download Full-text

Antioxidant, Antiapoptotic and Inflammatory Effects of Interleukin-18 Binding Protein on Kidney Damage Induced by Hepatic Ischemia Reperfusion

The American Journal of the Medical Sciences ◽

10.1016/j.amjms.2016.02.017 ◽

2016 ◽

Vol 351 (6) ◽

pp. 607-615 ◽

Cited By ~ 4

Author(s):

Yucel Gonul ◽

Mustafa Ozsoy ◽

Ahmet Kocak ◽

Ziya Taner Ozkececi ◽

Afra Karavelioglu ◽

...

Keyword(s):

Binding Protein ◽

Ischemia Reperfusion ◽

Kidney Damage ◽

Interleukin 18 ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

Download Full-text

CAAT/enhancer binding protein-homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice

Liver Transplantation ◽

10.1002/lt.25053 ◽

2018 ◽

Vol 24 (5) ◽

pp. 645-654 ◽

Cited By ~ 1

Author(s):

Seidai Wada ◽

Etsuro Hatano ◽

Tomoaki Yoh ◽

Naohiko Nakamura ◽

Yukihiro Okuda ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Binding Protein ◽

Ischemia Reperfusion ◽

Protein Deficiency ◽

Liver Ischemia ◽

Homologous Protein ◽

Enhancer Binding Protein

Download Full-text

Regulation of interaction of the iron-responsive element binding protein with iron-responsive RNA elements

Molecular and Cellular Biology ◽

10.1128/mcb.9.11.5055-5061.1989 ◽

1989 ◽

Vol 9 (11) ◽

pp. 5055-5061

Author(s):

D J Haile ◽

M W Hentze ◽

T A Rouault ◽

J B Harford ◽

R D Klausner

Keyword(s):

Binding Protein ◽

Reduced Form ◽

Scatchard Analysis ◽

Stem Loop ◽

Lower Affinity ◽

Translational Repressor ◽

High Affinity ◽

Iron Responsive Element ◽

Responsive Element

The 5' untranslated region of the ferritin heavy-chain mRNA contains a stem-loop structure called an iron-responsive element (IRE), that is solely responsible for the iron-mediated control of ferritin translation. A 90-kilodalton protein, called the IRE binding protein (IRE-BP), binds to the IRE and acts as a translational repressor. IREs also explain the iron-dependent control of the degradation of the mRNA encoding the transferrin receptor. Scatchard analysis reveals that the IRE-BP exists in two states, each of which is able to specifically interact with the IRE. The higher-affinity state has a Kd of 10 to 30 pM, and the lower affinity state has a Kd of 2 to 5 nM. The reversible oxidation or reduction of a sulfhydryl is critical to this switching, and the reduced form is of the higher affinity while the oxidized form is of lower affinity. The in vivo rate of ferritin synthesis is correlated with the abundance of the high-affinity form of the IRE-BP. In lysates of cells treated with iron chelators, which decrease ferritin biosynthesis, a four- to fivefold increase in the binding activity is seen and this increase is entirely caused by an increase in high-affinity binding sites. In desferrioxamine-treated cells, the high-affinity form makes up about 50% of the total IRE-BP, whereas in hemin-treated cells, the high-affinity form makes up less than 1%. The total amount of IRE-BP in the cytosol of cells is the same regardless of the prior iron treatment of the cell. Furthermore, a mutated IRE is not able to interact with the IRE-BP in a high-affinity form but only at a single lower affinity Kd of 0.7 nM. Its interaction with the IRE-BP is insensitive to the sulfhydryl status of the protein.

Download Full-text

Inhibition of the RNA binding protein HuR protects against cardiac ischemia/reperfusion injury by reducing inflammatory gene expression

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.lb515 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Samuel Slone ◽

Salma Fleifil ◽

Sarah Anthony ◽

Lisa Green ◽

Michelle L Nieman ◽

...

Keyword(s):

Gene Expression ◽

Reperfusion Injury ◽

Rna Binding ◽

Ischemia Reperfusion Injury ◽

Binding Protein ◽

Ischemia Reperfusion ◽

Rna Binding Protein ◽

Cardiac Ischemia ◽

Inflammatory Gene Expression ◽

Inflammatory Gene

Download Full-text

Ablation of the calpain-targeted site in cardiac myosin binding protein-C is cardioprotective during ischemia-reperfusion injury

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2019.03.006 ◽

2019 ◽

Vol 129 ◽

pp. 236-246 ◽

Cited By ~ 7

Author(s):

David Y. Barefield ◽

James W. McNamara ◽

Thomas L. Lynch ◽

Diederik W.D. Kuster ◽

Suresh Govindan ◽

...

Keyword(s):

Reperfusion Injury ◽

Protein C ◽

Ischemia Reperfusion Injury ◽

Binding Protein ◽

Ischemia Reperfusion ◽

Cardiac Myosin ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

Download Full-text

The calcium-binding protein complex S100A8/A9 has a crucial role in controlling macrophage-mediated renal repair following ischemia/reperfusion

Kidney International ◽

10.1038/ki.2014.216 ◽

2015 ◽

Vol 87 (1) ◽

pp. 85-94 ◽

Cited By ~ 32

Author(s):

Mark C. Dessing ◽

Alessandra Tammaro ◽

Wilco P. Pulskens ◽

Gwendoline J. Teske ◽

Loes M. Butter ◽

...

Keyword(s):

Protein Complex ◽

Calcium Binding ◽

Crucial Role ◽

Binding Protein ◽

Ischemia Reperfusion ◽

Calcium Binding Protein ◽

Renal Repair

Download Full-text

Phosphatidylethanolamine-Binding Protein 1 Ameliorates Ischemia-Induced Inflammation and Neuronal Damage in the Rabbit Spinal Cord

Cells ◽

10.3390/cells8111370 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1370 ◽

Cited By ~ 2

Author(s):

Kim ◽

Cho ◽

Jung ◽

Yoo ◽

Oh ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Neuronal Damage ◽

Binding Protein ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Prostaglandin F2α ◽

Proteomic Approach ◽

Phosphatidylethanolamine Binding Protein

In a previous study, we utilized a proteomic approach and found a significant reduction in phosphatidylethanolamine-binding protein 1 (PEBP1) protein level in the spinal cord at 3 h after ischemia. In the present study, we investigated the role of PEBP1 against oxidative stress in NSC34 cells in vitro, and ischemic damage in the rabbit spinal cord in vivo. We generated a PEP-1-PEBP1 fusion protein to facilitate the penetration of blood-brain barrier and intracellular delivery of PEBP1 protein. Treatment with PEP-1-PEBP1 significantly decreased cell death and the induction of oxidative stress in NSC34 cells. Furthermore, administering PEP-1-PEBP1 did not show any significant side effects immediately before and after ischemia/reperfusion. Administration of PEP-PEBP1 improved the Tarlov’s neurological score at 24 and 72 h after ischemia, and significantly improved neuronal survival at 72 h after ischemia based on neuronal nuclei (NeuN) immunohistochemistry, Flouro-Jade B staining, and western blot study for cleaved caspase 3. PEP-1-PEBP1 administration decreased oxidative stress based on malondialdehyde level, advanced oxidation protein products, and 8-iso-prostaglandin F2α in the spinal cord. In addition, inflammation based on myeloperoxidase level, tumor necrosis factor-α level, and high mobility group box 1 level was decreased by PEP-1-PEBP1 treatment at 72 h after ischemia. Thus, PEP-1-PEBP1 treatment, which decreases oxidative stress, inflammatory cytokines, and neuronal death, may be an effective therapeutic strategy for spinal cord ischemia.

Download Full-text