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)

Temperature-sensitive mutant of Moloney murine leukemia virus-TB (MoMuLV-ts1)-mediated neuronal death in mice is likely due to both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Cytotoxic mediators present in ts1-induced spongiform lesions may generate endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of a variety of neurodegenerative diseases. We investigated whether ER stress signaling is involved in ts1-mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-alpha. In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3. All of these events are markers of ER stress. We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls. Phosphorylated calmodulin-dependent protein kinase II-alpha was significantly increased, and was coexpressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes. Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca(2+)) accumulation in mitochondria. Together, these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca(2+) homeostasis. Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.
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PMID:Activation of endoplasmic reticulum stress signaling pathway is associated with neuronal degeneration in MoMuLV-ts1-induced spongiform encephalomyelopathy. 1509 14

Cardiac norepinephrine (NE) uptake is reduced in cardiomyopathy. This change is associated with a decrease of NE transporter (NET) receptor and can be reproduced in PC12 cells by extracellular NE. To study whether this effect of NE is mediated via impaired glycosylation and trafficking of NET in the endoplasmic reticulum (ER), we measured the distribution of glycosylated 80-kDa NET and unglycosylated 46-kDa NET in the membrane and cytosolic fractions of PC12 cells. We found that NE decreased glycosylated NET in both membrane and cytosolic fractions and increased cytosolic unglycosylated NET protein. Similar results were produced by tunicamycin and thapsigargin, two agents that induce ER stress by inhibiting N-glycosylation of membrane proteins and disrupting calcium homeostasis, respectively. Also, like the ER stressors, NE not only increased phosphorylation of both the alpha-subunit of eukaryotic initiation factor-2 and its upstream RNA-dependent protein kinase-like ER kinase over 12 h of treatment but also increased ER chaperone molecule glucose-regulated protein 78 and the nuclear transcription factor C/EBP homologous protein. Antioxidants superoxide dismutase and catalase prevented the downregulation of NET proteins and induction of ER stress signals produced by NE but not by tunicamycin or thapsigargin. The results indicate that the downregulation of membrane NET by NE is mediated by decreased N-glycosylation of NET proteins secondary to induction of ER stress pathways by NE-derived oxidative metabolites. Interventions involving the ER stress pathways may provide novel therapeutic strategies for the treatment of sympathetic dysfunction in heart failure.
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PMID:Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress. 1562 88

A monomethylated selenium metabolite, called methylseleninic acid (MSA), has recently been shown to cause global thiol redox modification of proteins. These changes represent a form of cellular stress due to protein misfolding or unfolding. An accumulation of aberrantly folded proteins in the endoplasmic reticulum (ER) triggers a defined set of transducers to correct the defects or commit the cells to apoptosis if the rescue effort is exhausted. Treatment of PC-3 human prostate cancer cells with MSA was found to induce a number of signature ER stress markers: (a) the survival/rescue molecules such as phosphorylated protein kinase-like ER-resident kinase (phospho-PERK), phosphorylated eukaryotic initiation factor-2alpha (phospho-eIF2alpha), glucose-regulated protein (GRP)-78, and GRP94; and (b) the apoptotic molecules such as caspase-12, caspase-7, and CAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153). Additional evidence suggested that CHOP/GADD153 might be an important transcription factor in apoptosis induction by MSA. In general, a higher concentration of MSA was required to elicit the apoptotic markers compared with the rescue markers. The apoptotic markers increased proportionally with the dose of MSA, whereas the rescue markers failed to keep pace with the increasing challenge from MSA. GRP78 is the rheostat of the ER stress transducers. In GRP78-overexpressing cells, the ability of MSA to up-regulate phospho-PERK, phospho-eIF2alpha, GRP94, caspase-12, caspase-7, and CHOP/GADD153 was significantly muted. A generous supply of GRP78 would allow cells to cope better with ER stress, thereby improving the odds for survival and negating the commitment to apoptotic death. The present study thus provides strong evidence to support an important role of ER stress response in mediating the anticancer effect of selenium.
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PMID:Endoplasmic reticulum stress signal mediators are targets of selenium action. 1620 82

Redox modification of thiol/disulfide interchange in proteins by selenium could lead to protein unfolding. When this occurs in the endoplasmic reticulum (ER), a process known as unfolded protein response (UPR) is orchestrated for survival through activation of PERK-eIF2alpha (PERK: double-stranded RNA-activated protein kinase-like ER kinase; eIF2alpha: eucaryotic initiation factor 2alpha), ATFalpha (ATFalpha: activating transcription factor 6) and inositol requiring 1 (IRE1)-x-box-binding protein 1 (XBP1) signalings. All three UPR transducer pathways were upregulated very rapidly when PC-3 cells were exposed to selenium. These changes were accompanied by increased expression of UPR target genes, including immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa and CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene (CHOP/GADD153). Induction of BiP/GRP78, an ER-resident chaperone, is part of the damage control mechanism, while CHOP/GADD153 is a transcription factor associated with growth arrest and apoptosis in the event of prolonged ER stress. Knocking down BiP/GRP78 induction by small interference RNA produced a differential response of the three transducers to selenium, suggesting that the signaling intensity of each transducer could be fine-tuned depending on BiP/GRP78 availability. In the presence of selenium, CHOP/GADD153 expression was raised even higher by BiP/GRP78 knockdown. Under this condition, the selenium effect on wild-type p53-activated fragment p21 (p21(WAF)), cyclin-dependent kinase (CDK)1 and CDK2 was also magnified in a manner consistent with enhanced cell growth arrest. Additional experiments with CHOP/GADD153 siRNA knockdown strongly suggested that CHOP/GADD153 may play a positive role in upregulating the expression of p21(WAF) in a p53-independent manner (PC-3 cells are p53 null). Collectively, the above findings support the idea that UPR could be an important mechanism in mediating the anticancer activity of selenium.
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PMID:Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. 1620 45

Enhanced endoplasmic reticulum (ER) stress leads to cell death in various pathophysiological situations. During a search for compounds that regulate ER stress, we identified methoxyflavones, a group of flavonoids, as strong protective agents against ER stress. Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2alpha and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER. The protective effect of methoxyflavones was enhanced by agents that increase intracellular cAMP levels such as forskolin, dibutyryl-cAMP and IBMX, but suppressed by the protein kinase A (PKA) inhibitor H-89, suggesting involvement of the PKA pathway in the regulation of ER stress by methoxyflavones. Consistent with the results in cultured cells, pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress. These results suggest that methoxyflavones play an important role in the regulation of ER stress and could be a therapeutic target for the ER stress-related diseases.
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PMID:Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. 1697 92

Curcumin has been shown to induce apoptosis in many cancer cells. However, the molecular mechanism(s) responsible for curcumin-induced apoptosis is not well understood and most probably involves several pathways. In HL-60 cells, curcumin induced apoptosis and endoplasmic reticulum (ER) stress as evidenced by the survival molecules such as phosphorylated protein kinase-like ER-resident kinase, phosphorylated eukaryotic initiation factor-2alpha, glucose-regulated protein-78, and the apoptotic molecules such as caspase-4 and CAAT/enhancer binding protein homologous protein (CHOP). Inhibition of caspase-4 activity by z-LEVD-FMK, blockage of CHOP expression by small interfering RNA, and treatment with salubrinal, an ER inhibitor, significantly reduced curcumin-induced apoptosis. Removing two double bonds in curcumin, which was speculated to form Michael adducts with thiols in secretory proteins, resulted in a loss of the ability of curcumin to induce apoptosis as well as ER stress. Thus, the present study shows that curcumin-induced apoptosis is associated with its ability to cause ER stress.
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PMID:Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells. 1719 82

A recent clinical trial (Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. Fertil Steril 87: 1399-1412, 2007) has demonstrated that the selective progesterone receptor modulator asoprisnil efficiently causes the shrinkage of uterine leiomyoma. The present study was conducted to examine whether asoprisnil elicits endoplasmic reticulum (ER) stress-induced apoptosis in cultured human uterine leiomyoma cells. After subculture in phenol red-free DMEM supplemented with 10% FBS for 120 h, cultured cells were stepped down to serum-free conditions with or without graded concentrations of asoprisnil. ER stress-associated and apoptosis-related proteins were assessed by reverse transcription-PCR analysis or Western blot analysis. RNA interference of growth-arrest- and DNA-damage-inducible gene 153 (GADD153) was performed using small interfering RNA. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL)-positive rates were assessed by TUNEL assay. Compared with untreated control cultures, treatment with 10(-7) M asoprisnil significantly (P < 0.05) increased the protein contents of ubiquitin at 2 h and phospho-double-stranded RNA-activated protein kinase-like ER kinase, phospho-eukaryotic initiation factor 2alpha, activating transcription factor 4, and glucose-regulated protein 78 kDa at 4 h, followed by the significant (P < 0.05) increase in GADD153 protein content at 6 h and cleaved poly(adenosine 5'-diphosphate ribose)polymerase (PARP) at 8 h. RNA interference of GADD153 suppressed protein contents of asoprisnil-induced cleaved PARP, Bax, Bak, GADD34, and tribbles-related protein 3 (TRB3) and TUNEL-positive rate but attenuated asoprisnil-induced reduction in Bcl-2 protein content in cultured leiomyoma cells. These results suggest that asoprisnil elicits ER stress-induced apoptosis in cultured leiomyoma cells and that GADD153 plays a role in asoprisnil-induced apoptosis by modulating the Bcl-2 family of proteins, GADD34, and TRB3.
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PMID:Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells. 1765 52

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

The chaperone glucose-regulated protein, 78/immunoglobulin binding protein (GRP78/Bip), protects cells from cytotoxicity induced by DNA damage or endoplasmic reticulum (ER) stress. In this study, we showed that GRP78 is a major inducible protein in human non-small cell lung cancer H460 cells treated with ER stress inducers, including A23187 and thapsigargin. AEBSF, an inhibitor of serine protease, diminished GRP78 induction, enhanced mitochondrial permeability, and augmented apoptosis in H460 cells during ER stress. Simultaneously, AEBSF promoted Raf-1 degradation and suppressed phosphorylation of Raf-1 at Ser338 and/or Tyr340 during ER stress. Coimmunoprecipitation assays and subcellular fractionations showed that GRP78 associated and colocalized with Raf-1 on the outer membrane of mitochondria, respectively. While treatment of cells with ER stress inducers inactivated BAD by phosphorylation at Ser75, a Raf-1 phosphorylation site; AEBSF attenuated phosphorylation of BAD, leading to cytochrome c release from mitochondria. Additionally, overexpression of GRP78 and/or Raf-1 protected cells from ER stress-induced apoptosis. Taken together, our results indicate that GRP78 may stabilize Raf-1 to maintain mitochondrial permeability and thus protect cells from ER stress-induced apoptosis.
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PMID:GRP78 and Raf-1 cooperatively confer resistance to endoplasmic reticulum stress-induced apoptosis. 1806 32

Contrast medium (CM) induces a direct toxic effect on renal tubular cells. This toxic effect may have a role in the pathophysiology of CM-induced nephropathy. CM has been shown to affect the endoplasmic reticulum (ER)-related capacity. Unfolded protein response (UPR) is known as a prosurvival response to reduce the accumulation of unfolded proteins and restore normal ER function. However, the role of ER stress-related UPR in the CM-induced renal cell injury still remains unclear. In this study, we examined whether UPR participates in urografin (an ionic CM)-induced renal tubular cells apoptosis. Treatment with urografin in normal rat renal tubular cell line (NRK52E) markedly increased cell apoptosis and decreased cell viability with a dose- and time-dependent manner. The cell necrosis was not increased in urografin-treated cells. Urografin also enhance the induction of ER stress-related markers in NRK52E cells, including glucose-regulated protein (GRP)78 and GRP94 expressions, procaspase-12 cleavage, phosphorylation of PERK (PKR [double-stranded RNA-activated protein kinase]-like ER kinase), and eukaryotic initiation factor 2alpha (eIF2alpha). Salubrinal, a selective inhibitor of eIF2alpha dephosphorylation, effectively decreased urografin-induced cell apoptosis. Furthermore, transfection of GRP78-small interfering RNA in NRK52E cells significantly enhanced urografin-induced cell apoptosis. These results suggest that GRP78/eIF2alpha-related signals play a protective role during UPR, and the activation of ER stress-related UPR may play an important regulative role in urografin-induced renal tubular injury.
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PMID:The role of endoplasmic reticulum stress-related unfolded protein response in the radiocontrast medium-induced renal tubular cell injury. 2007 20


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