Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In response to different cellular stresses, a family of protein kinases phosphorylates eIF2alpha (alpha subunit of eukaryotic initiation factor-2), contributing to regulation of both general and genespecific translation proposed to alleviate cellular injury or alternatively induce apoptosis. Recently, we reported eIF2alpha(P) (phosphorylated eIF2alpha) in the brain during SE (status epilepticus) induced by pilocarpine in mice, an animal model of TLE (temporal lobe epilepsy) [Carnevalli, Pereira, Longo, Jaqueta, Avedissian, Mello and Castilho (2004) Neurosci. Lett. 357, 191-194]. We show in the present study that one eIF2alpha kinase family member, PKR (double-stranded-RNA-dependent protein kinase), is activated in the cortex and hippocampus at 30 min of SE, reflecting the levels of eIF2alpha(P) in these areas. In PKR-deficient animals subjected to SE, eIF2alpha phosphorylation was clearly evident coincident with activation of a secondary eIF2alpha kinase, PEK/PERK (pancreatic eIF2alpha kinase/RNA-dependent-protein-kinase-like endoplasmic reticulum kinase), denoting a compensatory mechanism between the two kinases. The extent of eIF2alpha phosphorylation correlated with the inhibition of protein synthesis in the brain, as determined from polysome profiles. We also found that C57BL/6 mice, which enter SE upon pilocarpine administration but are more resistant to seizure-induced neuronal degeneration, showed very low levels of eIF2alpha(P) and no inhibition of protein synthesis during SE. These results taken together suggest that PKR-mediated phosphorylation of eIF2alpha contributes to inhibition of protein synthesis in the brain during SE and that sustained high levels of eIF2alpha phosphorylation may facilitate ensuing cell death in the most affected areas of the brain in TLE.
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PMID:Phosphorylation of the alpha subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus. 1649 39

dsRNA-binding domains (dsRBDs) characterize an expanding family of proteins involved in different cellular processes, ranging from RNA editing and processing to translational control. Here we present evidence that Ebp1, a cell growth regulating protein that is part of ribonucleoprotein (RNP) complexes, contains a dsRBD and that this domain mediates its interaction with dsRNA. Deletion of Ebp1's dsRBD impairs its localization to the nucleolus and its ability to form RNP complexes. We show that in the cytoplasm, Ebp1 is associated with mature ribosomes and that it is able to inhibit the phosphorylation of serine 51 in the eukaryotic initiation factor 2 alpha (eIF2alpha). In response to various cellular stress, eIF2alpha is phosphorylated by distinct protein kinases (PKR, PERK, GCN2, and HRI), and this event results in protein translation shut-down. Ebp1 overexpression in HeLa cells is able to protect eIF2alpha from phosphorylation at steady state and also in response to various treatments. We demonstrate that Ebp1 interacts with and is phosphorylated by the PKR protein kinase. Our results demonstrate that Ebp1 is a new dsRNA-binding protein that acts as a cellular inhibitor of eIF2alpha phosphorylation suggesting that it could be involved in protein translation control.
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PMID:Ebp1 is a dsRNA-binding protein associated with ribosomes that modulates eIF2alpha phosphorylation. 1663 6

B lymphocyte-induced maturation protein-1 (BLIMP-1) acts during differentiation of B cells and monocytes, but was originally identified as a repressor of the IFN-beta promoter induced during viral infection. A central regulator of the intracellular response to viral infection is the interferon-inducible double-stranded RNA activated protein kinase (PKR). PKR belongs to a family of kinases that phosphorylate the eukaryotic translation initiation factor 2-alpha (eIF2alpha) and activate common downstream signaling pathways. PERK, the endoplasmic reticulum resident PKR-homologue, is activated during the unfolded protein response (UPR), a stress response involved in both macrophage activation and terminal B-cell differentiation. This suggested that BLIMP-1 might be a target of stress responses involving PERK. We demonstrate that BLIMP-1 is rapidly up-regulated during the UPR in human myeloid and B-cell lines. This response is conserved in murine B-cells and murine macrophages, in which mimics of physiological stress and classical activation stimuli also induce Blimp-1. During the UPR, BLIMP-1 mRNA is induced at the level of transcription. This response is dependent on an intact PERK signaling pathway, independent of new protein synthesis and blocked by an inhibitor of NF-kappaB. Our data provide evidence for a novel pathway linking cellular stress to BLIMP-1, a regulator of differentiation in macrophages and B cells.
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PMID:BLIMP-1 is a target of cellular stress and downstream of the unfolded protein response. 1670 3

Oxygen supports the life of all aerobic organisms and virtually every cell type is capable of sensing decreased tissue oxygenation or hypoxia. Hypoxic microenvironments are known to exist within developing solid tumors as a result of insufficient vascular delivery of oxygen, which can limit the efficient growth and spread of the malignancy. On the other hand, clinical and experimental evidence has demonstrated that reduction in tumor blood flow can diminish the efficacy of standard anticancer therapeutics including radiotherapy and chemotherapy. Indeed, low oxygenation can accelerate malignant progression and metastasis resulting in poorer prognosis irrespective of the chosen treatment regiment. We and others have shown that tumor cells cultured under hypoxic conditions and cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). One of the key master switches in the ISR is the dynamically regulated protein kinase known as PERK. Tumors that lack PERK activity are small and compromised in their ability to translate mRNAs involved in angiogenesis and tumor survival. PERK can be activated by a number of distinct endoplasmic reticulum (ER) stress as well as hypoxia and promotes a tumor microenvironment that favors the formation of functional microvessels and ultimately tumor growth. We hypothesize that ER stress induced by sub-lethal doses of anti-cancer therapeutics could actually facilitate tumor progression by activation of the ISR. We propose that inhibitors of PERK may synergize with a variety of cancer therapeutics that directly or indirectly induce the ISR.
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PMID:Novel therapeutic target: the PERKs of inhibiting the integrated stress response. 1721 86

The IFN-induced double-stranded RNA-dependent protein kinase (PKR) is one of the four mammalian serine-threonine kinases (the three others being HRI, GCN2 and PERK) that phosphorylate the eIF2 alpha translation initiation factor, in response to stress signals, mainly as a result of viral infections. eIF2 alpha phosphorylation results in arrest of translation of both cellular and viral mRNAs, an efficient way to inhibit virus replication. The particularity of PKR is to activate by binding to dsRNA through two N terminal dsRNA binding motifs (dsRBM). PKR activation during a viral infection represents a threat for several viruses, which have therefore evolved to express PKR inhibitors, such as the Vaccinia E3L and K3L proteins. The function of PKR can also be regulated by cellular proteins, either positively (RAX/PACT; Mda7) or negatively (p58IPK, TRBP, nucleophosmin, Hsp90/70). PKR can provoke apoptosis, in part through its ability to control protein translation, but the situation appears to be more complex, as NF-kappaB, ATF-3 and p53 have also been implicated. PKR-induced apoptosis involves mainly the FADD/caspase 8 pathway, while the mitochondrial APAF/caspase 9 pathway is also engaged. As a consequence of the effects of PKR on translation, transcription and apoptosis, PKR can function to control cell growth and cell differentiation, and its activity can be controlled by the action of several oncogenes.
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PMID:The dsRNA protein kinase PKR: virus and cell control. 1745 62

Sustained ER stress leads to apoptosis. However, the exact mechanism still remains to be elucidated. Here, we demonstrate that the double strand RNA-dependent protein kinase (PKR) is involved in the ER stress-mediated signaling pathway. ER stress rapidly activated PKR, inducing the phosphorylation of eIF2alpha, followed by the activation of the ATF4/CHOP pathway. ER-stress-mediated eIF2alpha/ATF4/CHOP signaling and associated cell death was markedly reduced by PKR knockdown. We also found that PKR activation was mediated by PACT, the expression of which was elevated by ER-stress. These results indicate that the ER-stress-mediated eIF2alpha/ATF4/CHOP/cell death pathway is, to some degree, dependent on PACT-mediated PKR activation apart from the PERK pathway.
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PMID:The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis. 1771 68

To ensure cellular survival to ER (endoplasmic reticulum) stress, PERK [PKR (double-stranded-RNA-dependent protein kinase)-like ER kinase], an ER transmembrane kinase, is activated as part of the unfolded protein response. PERK is highly expressed in pancreatic beta-cells and is essential in the beta-cell's development, differentiation and function. However, chronic activation of PERK can induce cell death, and its activation has been implicated in both Type 1 and Type 2 diabetes. This short review aims to provide an insight into our current understanding of the role of PERK in the life and death of the beta-cell.
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PMID:PERK in the life and death of the pancreatic beta-cell. 1795 13

The endoplasmic reticulum (ER)-resident protein kinase PERK attenuates protein synthesis in response to ER stress through the phosphorylation of translation initiation factor eIF2alpha at serine 51. ER stress induces PERK autophosphorylation at several serine/threonine residues, a process that is required for kinase activation and phosphorylation of eIF2alpha. Herein, we demonstrate that PERK also possesses tyrosine kinase activity. Specifically, we show that PERK is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of PERK, is essential for autocatalytic activity. That is, mutation of Tyr-615 to phenylalanine compromises the autophosphorylation capacity of PERK and the phosphorylation of eIF2alpha in vitro and in vivo. The Y615F mutation also impairs the ability of PERK to induce translation of ATF4. Immunoblot analyses with a phosphospecific antibody confirm the phosphorylation of PERK at Tyr-615 both in vitro and in vivo. Thus, our data classify PERK as a dual specificity kinase whose regulation by tyrosine phosphorylation contributes to its optimal activation in response to ER stress.
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PMID:Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation. 1799 6

In the present study, we demonstrate that, in pancreatic beta-cells, eIF2alpha (eukaryotic initiation factor 2alpha) phosphorylation in response to a decrease in glucose concentration is primarily mediated by the activation of PERK [PKR (protein kinase RNA activated)-like endoplasmic reticulum kinase]. We provide evidence that this increase in PERK activity is evoked by a decrease in the energy status of the cell via a potentially novel mechanism that is independent of IRE1 (inositol requiring enzyme 1) activation and the accumulation of unfolded nascent proteins within the endoplasmic reticulum. The inhibition of eIF2alpha phosphorylation in glucose-deprived cells by the overexpression of dominant-negative PERK or an N-terminal truncation mutant of GADD34 (growth-arrest and DNA-damage-inducible protein 34) leads to a 53% increase in the rate of total protein synthesis. Polysome analysis revealed that this coincides with an increase in the amplitude but not the number of ribosomes per mRNA, indicating that eIF2alpha dephosphorylation mobilizes hitherto untranslated mRNAs on to polysomes. In summary, we show that PERK is activated at low glucose concentrations in response to a decrease in energy status and that this plays an important role in glucose-regulated protein synthesis in pancreatic beta-cells.
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PMID:A decrease in cellular energy status stimulates PERK-dependent eIF2alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells. 1805 27

We have further defined mechanism(s) by which 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide [OSU-03012 (OSU)], a derivative of the cyclooxygenase-2 (COX2) inhibitor celecoxib but lacking COX2 inhibitory activity, kills transformed cells. In cells lacking expression of protein kinase R-like endoplasmic reticulum kinase (PERK(-/-)), the lethality of OSU was attenuated. OSU enhanced the expression of Beclin 1 and ATG5 and cleavage of pro-caspase 4 in a PERK-dependent fashion and promoted the Beclin 1- and ATG5-dependent formation of vacuoles containing LC3, followed by a subsequent caspase 4-dependent cleavage of cathepsin B and a cathepsin B-dependent formation of low pH intracellular vesicles; cathepsin B was activated and released into the cytosol and genetic suppression of caspase 4, cathepsin B, or apoptosis-inducing factor function significantly suppressed cell killing. In parallel, OSU caused PERK-dependent increases in 70-kDa heat shock protein (HSP70) expression and decreases in 90-kDa heat shock protein (HSP90) and Grp78/BiP expression. Changes in HSP70 expression were post-transcriptional. Knock-down or small-molecule inhibition of HSP70 expression enhanced OSU toxicity, and overexpression of HSP70 suppressed OSU-induced low pH vesicle formation and lethality. Our data demonstrate that OSU-03012 causes cell killing that is dependent on PERK-induced activation of multiple toxic proteases. OSU-03012 also increased expression of HSP70 in a PERK-dependent fashion, providing support for the contention that OSU-03012-induced PERK signaling promotes both cell survival and cell death processes.
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PMID:OSU-03012 stimulates PKR-like endoplasmic reticulum-dependent increases in 70-kDa heat shock protein expression, attenuating its lethal actions in transformed cells. 1818 81


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