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)

Disruption of calcium homeostasis, inhibition of protein glycosylation, and reduction of disulfide bonds provoke accumulation of unfolded protein in the endoplasmic reticulum (ER), and are therefore a type of 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, GRP94 and protein disulfide isomerase to facilitate protein folding. This induction system is termed the unfolded protein response. Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6.
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PMID:The unfolded protein response and Alzheimer's disease. 1140 43

Cartilage oligomeric matrix protein (COMP), a large pentameric glycoprotein and member of the thrombospondin (TSP) group of extracellular proteins, is found in the territorial matrix surrounding chondrocytes. More than 50 unique COMP mutations have been identified as causing two skeletal dysplasias: pseudoachondroplasia (PSACH); and multiple epiphyseal dysplasia (EDM1). Recent studies suggest that calcium-binding and calcium-induced protein folding differ between wild type and mutant proteins, and abnormal processing of the mutant COMP protein contributes to the characteristic enlarged lamellar appearing rER cisternae in PSACH and EDMI chondrocytes in vivo and in vitro. Towards the goal of delineating the pathogenesis of PSACH and EDM1, in-vivo PSACH growth plate and in-vitro PSACH chondrocytes cultured in alginate beads were examined to identify and localize the chaperone proteins participating in the processing of the retained extracellular matrix proteins in the PSACH rER. Aggrecan was localized to both the rER cisternae and matrix while COMP and type IX collagen were only found in the rER. Type II collagen was solely found in the ECM suggesting that it is processed and transported differently from other retained ECM proteins. Five chaperone proteins: BiP (Grp78); calreticulin (CRT); protein disulfide (PDI); ERp72; and Grp94, demonstrated immunoreactivity in the enlarged PSACH cisternae and the short rER channels of chondrocytes from both in-vivo and in-vitro samples. The chaperone proteins cluster around the electron dense material within the enlarged rER cisternae. CRT, PDI and GRP94 AB-gold particles appear to be closely associated with COMP. Immunoprecipitation and Western blot, and Fluorescence Resonance Energy Transfer (FRET) analyses indicate that CRT, PDI and GRP94 are in close proximity to normal and mutant COMP and BiP to mutant COMP. These results suggest that these proteins play a role in the processing and transport of wild type COMP in normal chondrocytes and in the retention of mutant COMP in PSACH chondrocytes.
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PMID:Calreticulin, PDI, Grp94 and BiP chaperone proteins are associated with retained COMP in pseudoachondroplasia chondrocytes. 1147 Apr 1

1. A combination of patch clamp, confocal microscopy and immunohistochemistry was used to examine the spatial properties of Ca2+ signalling in the rat megakaryocyte, a non-excitable cell type in which membrane potential can markedly modulate agonist-evoked Ca2+ release. 2. Intracellular calcium ion concentration ([Ca2+]i) increases, stimulated by both ADP and depolarisation, frequently originated from a peripheral locus and spread as a wave throughout the cell. Spatially restricted [Ca2+]i increases, consistent with elementary Ca2+ release events, were occasionally observed prior to ADP-evoked waves. 3. ADP- and depolarisation-evoked Ca2+ waves travelled approximately twice as fast around the periphery of the cell compared to across its radius, leading to a curvilinear wavefront. There was no significant difference between wave velocities generated by the two stimuli. 4. Immunohistochemical staining of type III IP3 receptors, the endoplasmic reticulum-specific protein GRP78/BiP and calreticulin indicated a major peripheral location of the cellular Ca2+ stores which probably accounts for the accelerated wave velocity at the cell periphery. 5. These data demonstrate that [Ca2+]i increases, stimulated by depolarisation or the agonist ADP, have indistinguishable spatial properties, providing evidence that similar underlying mechanisms are responsible for their generation.
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PMID:Depolarisation-evoked Ca2+ waves in the non-excitable rat megakaryocyte. 1173 71

Platelet-derived growth factor (PDGF) is established to function importantly in the growth, development, and function of most cardiovascular tissues. However, evidence that the factor participates directly in the growth and development of the mammalian myocardium is lacking. H9c2 rat embryonic ventricular myocytes were found to respond to PDGF-BB with a rapid mobilization of cell-associated Ca2+ and increased rates of protein synthesis, followed by markedly increased rates of DNA synthesis. PDGF acted as a full mitogen for these myocytes. Evidence is provided that documents the expression of classical PDGF-beta, but not PDGF-alpha, receptors in H9c2 cells. Scatchard analysis revealed the presence of 44,000 beta-receptors per myocyte. Cell shortening and clustering of plasmalemmal beta-receptors occurred within 30 min of exposure to PDGF-BB. Treatment was also associated with a transient increase in the rate of synthesis of GRP78/BiP, consistent with a transitory release of Ca2+ from the sarcoplasmic/endoplasmic reticulum [S(E)R]. Increased rates of protein synthesis at early times of PDGF treatment were additive with those occurring in response to arginine vasopressin, indicating different mechanisms of translational upregulation by these agents. The mitogenic effects of PDGF were delayed by vasopressin, which causes H9c2 myocytes to undergo hypertrophy while promoting the persistent depletion of S(E)R Ca2+ stores. In the presence of PDGF, vasopressin did not induce hypertrophy. As compared to untreated myocytes, DNA synthesis in PDGF-treated myocytes was optimized at lower extracellular Ca2+ concentrations and was significantly less sensitive to inhibition by ionomycin. H9c2 cells appear to provide a useful embryonic cardiomyocyte model in which to examine both PDGF-activated proliferative and vasopressin-activated hypertrophic events and the importance of transient vs. sustained Ca2+ release in these events.
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PMID:Functional receptor for platelet-derived growth factor in rat embryonic heart-derived myocytes: role of sequestered Ca2+ stores in receptor signaling and antagonism by arginine vasopressin. 1183 99

Malfolded protein formation and perturbance of calcium homoeostasis results in the induction of the endoplasmic reticulum (ER) chaperone protein, namely the 78 kDa glucose-regulated protein (GRP78)/immunoglobulin heavy-chain binding protein. Various ER stress inducers can activate grp78, but signal transduction mechanisms are not well understood. We report in the present study that the induction of endogenous grp78 mRNA by the amino acid analogue azetidine (AzC) requires the integrity of a signal transduction pathway mediated by p38 mitogen-activated protein kinase (p38 MAPK). In contrast, induction of grp78 by thapsigargin that depletes the ER calcium storage can occur even when the p38 MAPK pathway is blocked. Treatment of cells with AzC results in the sustained activation of p38 MAPK. We identified an ER transmembrane activating transcription factor 6 (ATF6) as a target of p38 MAPK phosphorylation in AzC-treated cells. ATF6 undergoes proteolytic cleavage on AzC treatment, releasing a nuclear form that is an activator of the grp78 promoter. We show here that constitutively active mitogen-activated protein kinase kinase 6, a selective p38 MAPK activator, enhances the ability of the nuclear form of ATF6 to transactivate the grp78 promoter. Our results provide direct evidence that different ER stress inducers use diverse pathways to activate grp78 and that in addition to activation by proteolytic cleavage, ATF6 undergoes specific ER stress-induced phosphorylation. We propose that phosphorylation of ATF6 is a novel mechanism for augmenting its potential as a transcription activator.
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PMID:Requirement of the p38 mitogen-activated protein kinase signalling pathway for the induction of the 78 kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein by azetidine stress: activating transcription factor 6 as a target for stress-induced phosphorylation. 1207 52

Sixteen clones, recently isolated from the PC12 nerve cell line, were analysed for a variety of markers and activities. Two endoplasmic reticulum (ER) luminal markers, the chaperone protein BiP and the major Ca2+ storage protein calreticulin, as well as the 40-kD rough ER membrane marker and the plus-end-directed mirotubule motor protein, kinesin, were found to be expressed at similar levels. These results suggest that the size of the ER, the function of microtubules and the capacity of the rapidly exchanging Ca2+ store do not change substantially among the clones. Other proteins expressed at comparable levels were synapsin I and IIa, members of a nerve cell-specific protein family known to bind synaptic vesicles to the cytoskeleton. In contrast, another ER membrane protein, calnexin, and the markers of secretory organelles were found to vary markedly. One clone (clone 27) completely lacked both chromogranin B and secretogranin II, the proteins contained within dense granules, and synaptophysin, a marker of clear vesicles. Other clones expressed these markers to variable and apparently mutually unrelated levels. Marked variability was observed also in the uptake of exogenous catecholamines, in their release both at rest and after stimulation, and in nerve growth factor-induced differentiation. These results provide indirect information about the mechanisms that regulate the expression of structures and activities in PC12 cells. Of particular interest is clone 27, which appears globally incompetent for regulated secretion and might therefore be a valuable tool for the study of this activity in a nerve cell.
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PMID:Differential Expression of Markers and Activities in a Group of PC12 Nerve Cell Clones. 1210 30

Activation of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of caspase-12 activation and its effect on calcium homeostasis in an ER stress-induced model of apoptosis. The human liver-derived cell line, Huh7, was treated with thapsigargin (TG) to induce ER stress. Typical morphologic changes of ER stress preceded development of apoptotic changes, including DNA fragmentation and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP), as well as activation of caspase-3 and -7. Elevation of intracellular calcium levels without loss of mitochondrial membrane potential (MMP) was shown using Fluo-3/Fura-red labeling and flow cytometry, and confirmed by induction of Bip/GRP78, a calcium-dependent chaperon of ER lumen. These changes were accompanied by procaspase-12 processing. TUDCA abolished TG-induced markers of ER stress; reduced calcium efflux, induction of Bip/GRP78, and caspase-12 activation; and subsequently inhibited activation of effector caspases and apoptosis. In conclusion, we propose that mitochondria play a secondary role in ER-mediated apoptosis and that TUDCA prevents apoptosis by blocking a calcium-mediated apoptotic pathway as well as caspase-12 activation. This novel mechanism of TUDCA action suggests new intervention methods for ER stress-induced liver disease.
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PMID:Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation. 1219 51

We have studied the localization of functional components of cellular Ca2+ transport and storage and the effects of thapsigargin (TG), a specific inhibitor of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), with respect to the p58-containing pre-Golgi intermediate compartment (IC). The depletion of Ca2+ stores in normal rat kidney (NRK) cells by TG abolished the retention of the KDEL-containing, Ca2+-binding, luminal ER chaperones GRP94/endoplasmin and GRP78/BiP, and resulted in the appearance of the proteins in the culture medium before inducing their synthesis. Immunolocalization of GRP94 in TG-treated cells showed that the protein was transported to the Golgi complex and, in parallel, the KDEL receptor was redistributed from the Golgi to p58-positive IC structures, but was not transported further to the ER. Similarly, p58 that normally cycles between the ER, IC, and cis-Golgi, was largely depleted from the cell periphery and arrested in large-sized IC elements and numerous vesicles or buds in the Golgi region, showing that TG selectively blocks its recycling from the IC back to the ER. Importantly, cell fractionation analyses and confocal fluorescence microscopy provided evidence that the IC elements in unperturbed cells contain SERCA and a considerable pool of GRP94. Thus, the observed effects of TG on protein retention and recycling can be explained by a change in the luminal Ca2+ concentration of the IC. Moreover, the compositional properties of the IC elements suggest that they participate in intracellular Ca2+ storage.
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PMID:Colocalization of Ca2+-ATPase and GRP94 with p58 and the effects of thapsigargin on protein recycling suggest the participation of the pre-Golgi intermediate compartment in intracellular Ca2+ storage. 1241 24

DNA damage is believed to be the main cause of the antiproliferative effect of cisplatin, a cornerstone agent in anticancer therapy. However, cisplatin can be expected to react also with nucleophiles other than DNA. Using enucleated cells (cytoplasts) we demonstrate here that cisplatin-induced apoptotic signaling may occur independently of DNA damage. Cisplatin-induced caspase-3 activation in cytoplasts required calcium and the activity of the calcium-dependent protease calpain. It is known that calpain activation may be associated with endoplasmic reticulum (ER) stress, suggesting that the ER is a cytosolic target of cisplatin. Consistent with this hypothesis, cisplatin induced calpain-dependent activation of the ER-specific caspase-12 in cytoplasts as well as in intact cells. Cisplatin also induced increased expression of Grp78/BiP, another marker of ER stress. By contrast, the DNA-damaging topoisomerase II inhibitor etoposide did not induce apoptotic signaling in cytoplasts nor ER stress in intact cells. We have thus identified a novel mechanism of action of cisplatin. The results have implications for the understanding of resistance mechanisms as well as the unique efficiency of this drug.
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PMID:Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. 1250 15

Mammalian skin is regularly exposed to different environmental stresses, each of which results in specific compensatory changes in protein expression that can be assessed by proteomic analysis. We have established a reference proteome map of BALB/c murine skin allowing the resolution of greater than 500 protein spots in a single two-dimensional polyacrylamide gel. Forty-four protein spots, corresponding to 28 different cutaneous proteins, were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the Mascot online database searching algorithm. Twenty-five proteins were expressed at higher levels in the epidermis, whereas only nine were found predominantly in the subepidermal tissues. A subset of protein spots exhibited strain-specific expression. Proteins of diverse function were identified, including those involved in stress response, apoptosis, growth inhibition, the maintenance of structural integrity, translational control, energy metabolism, calcium binding, cholesterol transport, and the scavenging of free radicals. Prohibitin expression was detected cutaneously, with more abundant protein and mRNA levels in the epidermis. Five molecular chaperones including protein di-sulfide isomerase, 78 kDa glucose-regulated protein precursor, heat shock protein 60 (HSP60), HSP70, and HSP27 were also identified. Of these, HSP27 expression was confined mainly to the epidermis, and expression of protein disulfide isomerase was found primarily in the subepidermal tissues. Proteomic analysis of skin following heat or cold shock resulted in increased levels of HSP27, HSP60, and HSP70 suggesting involvement of these chaperones in the cutaneous response mechanism to temperature stress. These data establish numerous reference markers within the proteome map of murine skin and provide an important framework for future efforts aimed at characterization of the epidermal and subepidermal responses to environmental changes.
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PMID:Comparative proteomic profiling of murine skin. 1283 95


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