Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R-like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK-/- cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B-dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival.
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PMID:Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells. 1828 15

Many metabolic reactions in the endoplasmic reticulum (ER) require high levels of energy in the form of ATP, which is important for cell viability. Here, we report on an adenine nucleotide transporter residing in the ER membranes of Arabidopsis thaliana (ER-ANT1). Functional integration of ER-ANT1 in the cytoplasmic membrane of intact Escherichia coli cells reveals a high specificity for an ATP/ADP antiport. Immunodetection in transgenic ER-ANT1-C-MYC-tag Arabidopsis plants and immunogold labeling of wild-type pollen grain tissue using a peptide-specific antiserum reveal the localization of this carrier in ER membranes. Transgenic ER-ANT1-promoter-beta-glucuronidase Arabidopsis lines show high expression in ER-active tissues (i.e., pollen, seeds, root tips, apical meristems, or vascular bundles). Two independent ER-ANT1 Arabidopsis knockout lines indicate a high physiological relevance of ER-ANT1 for ATP transport into the plant ER (e.g., disruption of ER-ANT1 results in a drastic retardation of plant growth and impaired root and seed development). In these ER-ANT1 knockout lines, the expression levels of several genes encoding ER proteins that are dependent on a sufficient ATP supply (i.e., BiP [for luminal binding protein] chaperones, calreticulin chaperones, Ca2+-dependent protein kinase, and SEC61) are substantially decreased.
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PMID:Identification of a novel adenine nucleotide transporter in the endoplasmic reticulum of Arabidopsis. 1829 23

Melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The studies by Yacoub et al. (Mol Cancer Ther 2008; 7:314-29) further defines the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that were dependent on activation of JNK1-3 with subsequent activation of BAX and the induction of mitochondrial dysfunction. Activation of JNK1-3 was dependent upon protein kinase R-like endoplasmic reticulum kinase (PERK) and GST-MDA-7 lethality was suppressed in PERK(-/-) cells. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or of BiP/GRP78, or by knockdown of ATG5 or Beclin 1 expression, but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin 1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data demonstrate that GST-MDA-7 induces an ER stress response that, via the induction of autophagy, is causal in the activation of pro-apoptotic pathways that converge on the mitochondrion and ultimately culminate in decreased glioma cell survival.
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PMID:PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells. 1829 61

Major questions on the biology of sleep include the following: what are the molecular functions of sleep; why can wakefulness only be sustained for defined periods before there is behavioral impairment; what genes contribute to the individual differences in sleep and the response to sleep deprivation? Behavioral criteria to define sleep have facilitated identification of sleep states in a number of different model systems: Drosophila, zebrafish, and Caenorhabditis elegans. Each system has unique strengths. Studies in these model systems are identifying conserved signaling mechanisms regulating sleep that are present in mammals. For example, the PKA-CREB signaling mechanism promotes wakefulness in Drosophila, mice, and C. elegans. Microarray studies indicate that genes whose expression is upregulated during sleep are involved in macromolecule biosynthesis (proteins, lipids [including cholesterol], heme). Thus, a key function of sleep is likely to be macromolecule synthesis. Moreover, in all species studied to date, there is upregulation of the molecular chaperone BiP with extended wakefulness. Sleep deprivation leads to cellular ER stress in brain and the unfolded protein response. Identification of genes regulating sleep has the potential for translational studies to elucidate the genetics of sleep and response to sleep deprivation in humans.
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PMID:Molecular mechanisms of sleep and wakefulness. 1859 93

Previously, using primary hepatocytes residing in early G1 phase, we demonstrated that expression of the cyclin-dependent kinase (CDK) inhibitor protein p21Cip-1/WAF1/mda6 (p21) enhanced the toxicity of deoxycholic acid (DCA) + MEK1/2 inhibitor. This study examined the mechanisms regulating this apoptotic process. Overexpression of p21 or p27(Kip-1) (p27) enhanced DCA + MEK1/2 inhibitor toxicity in primary hepatocytes that was dependent on expression of acidic sphingomyelinase and CD95. Overexpression of p21 suppressed MDM2, elevated p53 levels, and enhanced CD95, BAX, NOXA, and PUMA expression; knockdown of BAX/NOXA/PUMA reduced CDK inhibitor-stimulated cell killing. Parallel to cell death processes, overexpression of p21 or p27 profoundly enhanced DCA + MEK1/2 inhibitor-induced expression of ATG5 and GRP78/BiP and phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) and eIF2alpha, and it increased the numbers of vesicles containing a transfected LC3-GFP construct. Incubation of cells with 3-methyladenine or knockdown of ATG5 suppressed DCA + MEK1/2 inhibitor-induced LC3-GFP vesicularization and enhanced DCA + MEK1/2 inhibitor-induced toxicity. Expression of dominant negative PERK blocked DCA + MEK1/2 inhibitor-induced expression of ATG5, GRP78/BiP, and eIF2alpha phosphorylation and prevented LC3-GFP vesicularization. Knock-out or knockdown of p53 or CD95 abolished DCA + MEK1/2 inhibitor-induced PERK phosphorylation and prevented LC3-GFP vesicularization. Thus, CDK inhibitors suppress MDM2 levels and enhance p53 expression that facilitates bile acid-induced, ceramide-dependent CD95 activation to induce both apoptosis and autophagy in primary hepatocytes.
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PMID:Multiple cyclin kinase inhibitors promote bile acid-induced apoptosis and autophagy in primary hepatocytes via p53-CD95-dependent signaling. 2766 64

Zinc is an important dietary factor that regulates intestinal amino acid and protein metabolism in animals. Recent work with the piglet, an established animal model for studying human infant nutrition, has shown that supplementing high levels of zinc oxide (ZnO) to the diet ameliorates weaning-associated intestinal injury and growth retardation. However, the underlying mechanisms are largely unknown. This study tested the hypothesis that zinc supplementation affects expression of proteins related to glutathione metabolism and oxidative stress in the gut. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 22 up-regulated and 19 down-regulated protein spots in the jejunum of weanling piglets supplemented with ZnO (3,000 mg/kg Zn) compared with the control pigs (100 mg/kg Zn). These proteins are related to energy metabolism (increased level for succinyl-CoA transferase and decreased level for creatine kinase M-type); oxidative stress (decreased levels for 78 kDa glucose-regulated protein and glutathione-S-transferase-omega); and cell proliferation and apoptosis (increased levels for A-Raf-1 and calregulin). Consistent with the changes in protein expression, the ratio of reduced glutathione to oxidized glutathione was increased, whereas glutathione-S-transferase and glutathione peroxidase activities as well as the protein level of active caspase-3 were reduced in ZnO-supplemented piglets. Collectively, these results indicate that ZnO supplementation improves the redox state and prevents apoptosis in the jejunum of weaning piglets, thereby alleviating weaning-associated intestinal dysfunction and malabsorption of nutrients (including amino acids).
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PMID:Proteomic analysis reveals altered expression of proteins related to glutathione metabolism and apoptosis in the small intestine of zinc oxide-supplemented piglets. 1918 41

Most patients with Alzheimer's disease (AD) present decreased levels of melatonin, a day-night rhythm-related hormone. To investigate the role of melatonin deficiency in AD, we used constant illumination to interrupt melatonin metabolism and measured some of the AD-like alterations in rats. Concomitant with decreased serum melatonin, the rats developed spatial memory deficits, tau hyperphosphorylation at multiple sites, activation of glycogen synthase kinase-3 and protein kinase A, as well as suppression of protein phosphatase-1. Prominent oxidative damage and organelle lesions, demonstrated by increased expression of endoplasmic reticulum (ER) stress-related proteins including BiP/GRP78 and CHOP/GADD153, decreased number of rough ER and free ribosome, thinner synapses, and increased superoxide dismutase and monoamine oxidase were also observed in the light exposed rats. Simultaneous supplement of melatonin partially arrested the behavioral and molecular impairments. It is suggested that melatonin deficiency may be an upstream effector responsible for the AD-like behavioral and molecular pathologies with ER stress-involved mechanisms.
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PMID:Constant illumination induces Alzheimer-like damages with endoplasmic reticulum involvement and the protection of melatonin. 1922 18

Cytokeratin 19 (CK19) is widely used as a biomarker for the detection of disseminated tumor cells in blood and bone marrow, and its positivity is considered as an independent prognostication indicator in cancer patients. However, its role in breast cancer progression remains unknown. We had established a stable CK19-expressing clone in the CK19-negative BT549 human breast cancer cell line and found that CK19 expression in the BT549 cells caused cell cycle arrest, reduced cell motility and increased drug resistance. Further study revealed that CK19 expression regulated endoplasmic reticulum (ER) stress signaling by up-regulating p38/RNA-dependent protein kinase-like ER kinase (PERK)/p-eIF2alpha and 78 kDa glucose-regulated protein (Bip/GRP78), and down-regulating focal adhesion kinase (FAK). The level of ER protein 29 (ERp29) was shown to be decreased in the CK19-expressing BT549 cells by proteomic analyses and verified by Western blotting and RT-PCR. Pharmacological inhibition of p38 signaling by its specific inhibitor SB203580 or knockdown of p38 and transcription factor XBP-1 by siRNA in BT549/CK19 and MDA-MB-231 cells revealed that p38/XBP-1 signaling negatively regulated ERp29 expression. Our results indicated that CK19 modulates ER stress signaling and contributes to cell survival and dormancy in breast cancer cells.
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PMID:Cytokeratin 19 regulates endoplasmic reticulum stress and inhibits ERp29 expression via p38 MAPK/XBP-1 signaling in breast cancer cells. 1926 90

The endoplasmic reticulum (ER) membrane protein ERj1, a member of the Hsp40 family, was proposed to be a regulator of protein biogenesis at the ER. With its lumenal J-domain, ERj1 recruits the lumenal Hsp70-type chaperone BiP to newly synthesized polypeptide chains. Its cytosolic domain interacts with ribosomes and inhibits protein synthesis in its BiP-free state. Additionally, the cytosolic domain may act as a transcription factor. Recent proteomic data suggest that ERj1 is a target of phosphorylation. Since protein kinase CK2 is present on the ER surface, we addressed the question whether ERj1 is a substrate for CK2. We show that native ERj1 is phosphorylated by CK2. Using deletion mutants, ERj1 peptides, and a mutational analysis, the major phosphorylation site for CK2 was mapped to the conserved sequence motif SSDEE at amino acid residues 477-481, which is located in the cytosolic domain of ERj1.
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PMID:The ER-membrane-resident Hsp40 ERj1 is a novel substrate for protein kinase CK2. 1965 99


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