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)

Ribonucleoparticle-independent transport of precursor proteins into mammalian microsomes is stimulated by 70-kDa heat shock proteins (Hsc70) and an additional cytosolic protein. Here we addressed the question of whether other molecular chaperones can replace Hsc70 in facilitating protein transport into the endoplasmic reticulum. Specifically, we asked if members of the same family of stress proteins, i.e. the microsomal protein immunoglobulin heavy chain binding protein or the bacterial protein DnaK, can substitute for Hsc70. Furthermore, we investigated whether molecular chaperones with a proven role in protein folding and belonging to the other two major families of stress proteins, i.e. Hsp60 or Hsp90, can substitute for Hsc70. We show that none of these stress proteins was able to substitute for Hsc70 in facilitating protein transport into mammalian microsomes. GroEL (the bacterial member of the Hsp60 family) and Hsp90, however, competed with Hsc70 for binding of the non-native precursor protein. Therefore, we conclude that there are both substrate and functional specificity in the action of molecular chaperones.
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PMID:Hsc70, immunoglobulin heavy chain binding protein, and Hsp90 differ in their ability to stimulate transport of precursor proteins into mammalian microsomes. 809 9

The heat shock proteins (Hsp) are stress-responsive genes present in all species; increases of Hsp can confer chemotherapeutic resistance to certain cancers. The purpose of this study was to determine Hsp expression in human gastric, pancreatic and colon cancers. Gastric (n = 3), pancreatic (n = 6) and colon (n = 8) cancers were extracted for RNA and protein, and Northern and Western blots performed. We found that hsp70 and hsp27 mRNA levels were differentially expressed in the gastrointestinal cancers; mRNA expression closely correlated with protein levels suggesting regulation at the level of transcription. In addition, Hsp90 and BiP proteins were constitutively expressed in the gastrointestinal cancers. We conclude that the Hsp are differentially expressed in human gastric, pancreatic and colon cancers; these increases in Hsp occur constitutively and are not the result of physiological or environmental stresses. Increases of Hsp expression in cancer cells may enhance resistance and account for the altered sensitivity of certain gastrointestinal cancers to chemotherapeutic agents.
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PMID:Heat shock proteins are differentially expressed in human gastrointestinal cancers. 852 82

Human fibrinogen (340 kDa) is a dimer, with each identical half-molecule composed of three different polypeptides (Aalpha, 66 kDa; Bbeta, 55 kDa; and gamma, 48 kDa). To understand the mechanisms of chain assembly, a coupled in vitro transcription translation system capable of assembling fibrinogen chains was developed. Fibrinogen chain assembly was assayed in an expression system coupled to rabbit reticulocyte lysate in the presence or absence of dog pancreas microsomal membranes. Fibrinogen chain assembly required microsomal membranes and oxidized glutathione. Co-expression of two of the chains, Bbeta and gamma or Aalpha and gamma, yielded free chains and two-chain complexes. Unlike combinations of Aalpha with gamma and Bbeta with gamma, co-expression of Aalpha and Bbeta did not form a single two-chain complex but produced a mixture of two-chain complexes. Co-expression of all three chains yielded free chains, two-chain complexes, and higher molecular weight complexes that corresponded to a half-molecule and to fully formed fibrinogen. Upon treatment of this mixture with thrombin and factor XIIIa, a gamma.gamma dimer, similar to that obtained from cross-linked human fibrin, was produced, indicating that properly folded fibrinogen was formed in vitro. Molecular chaperones may participate in fibrinogen assembly, since antibodies to resident proteins of the endoplasmic reticulum (BiP, Hsp90, protein disulfide isomerase, and calnexin) co-precipitated the chaperones together with nascent fibrinogen chains and complexes.
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PMID:In vitro assembly of the component chains of fibrinogen requires endoplasmic reticulum factors. 879 16

Heat shock protein 72/73 (Hsp70) is a cytosolic molecular chaperone that carries out fundamental roles under both normal and stress situations. There is great interest in delineating the mechanisms whereby Hsp70 levels are regulated. We observed that N-acetyl-leucyl-leucyl-norleucinal (ALLN), a synthetic aldehydic tripeptide that inhibits proteasomes, markedly induced Hsp70 levels (up to 30-fold above base line in HepG2 cells and human endothelial cells). Induction of Hsp70 by ALLN was dose-dependent and not related to cell toxicity. ALLN selectively increased Hsp70 levels without affecting Hsp25, Hsp27, Hsp60, Hsp86, Hsp90, Hsp104, or Bip (immunoglobulin heavy chain binding protein) in HepG2 cells. ALLN induced Hsp70 not only by stabilizing the protein but also by dramatically increasing its synthesis. The modulation of Hsp70 synthesis by ALLN resulted from a rapid and marked increase in transcription of the hsp72 gene, since the induction of hsp72 mRNA was blocked in cells co-treated with actinomycin D. hsp72 mRNA levels were affected in a time-dependent manner by exposure to ALLN; significant elevations occurred within 60 min of treatment, and a decline to background levels was observed by 7 h of recovery. The ALLN-induced increase in hsp72 gene expression was associated with trimerization of the heat shock transcriptional factor (HSF1). ALLN did not affect the steady-state level of HSF1 protein. The effects of ALLN appeared to require de novo protein synthesis, since the induction of both HSF1 trimerization and hsp72 transcription was blocked by co-treatment with cycloheximide. When we tested a series of protease inhibitors, only the related aldehydic tripeptides, N-acetyl-leucyl-leucyl-methioninal and the proteasome inhibitor, Cbz-leucyl-leucyl-leucinal, induced Hsp70 levels. The specific proteasome inhibitor, lactacystin, which has a different structure, also induced Hsp70 levels. Overall, our results suggest that a rapidly turning over protein that is normally degraded by proteasomes may be involved in the regulation of Hsp70 synthesis via effects on the hsp70 transcriptional factor, HSF1.
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PMID:Evidence that a rapidly turning over protein, normally degraded by proteasomes, regulates hsp72 gene transcription in HepG2 cells. 879 47

High hydrostatic pressure (HP) has recently been shown to increase cellular heat shock protein 70 (Hsp70) level in a specific way that does not involve transcriptional activation of the gene, but rather the stabilisation of the mRNA for Hsp70. In this study, we investigated whether there are other observable changes caused by HP stress, and compared them with those induced by certain other forms of stressors. A chondrocytic cell line T/C28a4 was exposed to 30 MPa continuous HP, heat shock at 43 degrees C, and increased cytosolic calcium concentration by the addition of sarco-endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin (25 nM) or calcium ionophore A23187 (1 microM) in the cultures. The protein synthesis was studied by in vitro metabolic labelling followed by one- and two-dimensional polyacrylamide gel electrophoresis, and mass spectrometry was utilized to confirm the identity of the protein spots on two-dimensional gels. Continuous 30 MPa HP increased remarkably the relative labelling of Hsp70. Labelling of Hsp90 was also increased by 15-20%, although no clear change was evident at the protein level in Western blots. Elevated intracellular Ca(2+) concentration induced by thapsigargin and calcium ionophore A23187 increased mainly the synthesis of glucose-regulated protein 78 (Grp78/BiP), whereas Hsp70 and Hsp90 were decreased by the treatment. Heat shock was the strongest inducer of Hsp70 and Hsp90. This study further confirmed the induction of Hsp70 in chondrocytic cells exposed to high HP, but it also showed that calcium-mediated responses are unlikely to cause the stress response observed in the hydrostatically pressurized cells.
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PMID:Differential regulation of stress proteins by high hydrostatic pressure, heat shock, and unbalanced calcium homeostasis in chondrocytic cells. 1099 52

A number of clinical conditions are known to result in the induction of heat shock proteins, but detailed studies on stress response have focused mostly on heat shock as a model. We have analyzed the induction and intracellular distribution of heat shock proteins in a reversible adenosine triphosphate (ATP) depletion model of renal ischemia. Two Hsp70 homologues, Hsp70 in the cytoplasm and BiP in the endoplasmic reticulum (ER) lumen, were found significantly induced during the recovery phase of ATP depletion. Other members of the heat shock protein family, such as Hsp90, constitutive Hsc70, and a related protein Hop60, were not induced. The induction of stress proteins on ATP depletion differed from that after heat shock in the kinds of proteins elaborated, their induction kinetics, and their intracellular distributions. Biochemical fractionation and indirect immunofluorescence experiments indicated that Hsp70 was predominantly cytoplasmic in the recovery phase of ischemia-like stress. Velocity sedimentation on sucrose gradients showed that induced Hsp70 sedimented as small, soluble complexes, ranging in size from 4S20,w to 8S20,w. The results suggest a role for induced Hsp70 that may be different from one of protecting aggregated proteins as under heat shock and emphasize the need for their characterization in other clinical conditions that result in stress response.
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PMID:Induced hsp70 is in small, cytoplasmic complexes in a cell culture model of renal ischemia: a comparative study with heat shock. 1104 54

EGFRvIII is a mutant epidermal growth factor that promotes aggressive growth of glioblastomas. We made a plasmid that directed the expression of an EGFRvIII with three copies of the Flag epitope at its amino terminus. Flag-tagged EGFRvIII was expressed at the same levels as unmodified EGFRvIII, and showed the same subcellular localization. However, the Flag epitope could only be detected on EGFRvIII present in the endoplasmic reticulum; the epitope was covalently modified during trafficking of the receptor through the Golgi so that it was no longer recognized by anti-Flag antibody. This property was exploited to selectively purify nascent EGFRvIII from glioblastoma cells. Nascent EGFRvIII was found to copurify with a set of other proteins, identified by mass spectrometry as the two endoplasmic reticulum chaperones Grp94 and BiP, and the two cytosolic chaperones Hsc70 and Hsp90. The Hsp90-associated chaperone Cdc37 also co-purified with EGFRvIII, suggesting that Hsp90 binds EGFRvIII as a complex with this protein. Geldanamycin and radicicol, two chemically unrelated inhibitors of Hsp90, decreased the expression of EGFRvIII in glioblastoma cells. These studies show that nascent EGFRvIII in the endoplasmic reticulum associates with Hsp90 and Cdc37, and that the Hsp90 association is necessary to maintain expression of EGFRvIII.
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PMID:Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII. 1247 Oct 35

We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B chronic lymphocytic leukemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4-hour pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from healthy donors as well as those present in the CLL isolates were relatively resistant. GA, but not HMA, showed a modest cytoprotective effect toward CD34+ hematopoietic progenitors from normal bone marrow. The ability of bone marrow progenitors to form hematopoietic colonies was unaffected by pulse exposures to GA. Both GA and HMA synergized with chlorambucil and fludarabine in killing a subset of CLL isolates. GA- and HMA-induced apoptosis was preceded by the up-regulation of the stress-responsive chaperones Hsp70 and BiP. Both ansamycins also resulted in down-regulation of Akt protein kinase, a modulator of cell survival. The relative resistance of T lymphocytes and of CD34+ bone marrow progenitors to GA coupled with its ability to induce apoptosis following brief exposures and to synergize with cytotoxic drugs warrant further investigation of ansamycins as potential therapeutic agents in CLL.
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PMID:Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs. 1457 64

The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding enzymes involved in drug metabolism. Known ligands include polycyclic aromatic hydrocarbons, certain polychlorinated biphenyls, and the polyhalogenated dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin. Both polyhalogenated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin are potent promoters of rodent hepatocarcinogenesis in two-stage initiation-promotion experiments. Although several lines of evidence indicate the involvement of the AhR in toxic effects mediated by polyhalogenated biphenyls and dioxins, its involvement in tumor promotion has not been unequivocally proven. In the present study, a transgenic mouse line expressing a constitutively active AhR (CA-AhR) has been used to investigate the role of the AhR in hepatocarcinogenesis. Male AhR wild-type and CA-AhR-transgenic B6C3F1-mice were treated with a single injection of the hepatocarcinogen N-nitrosodiethylamine at 6 weeks of age and were subsequently kept untreated on control diet. Thirty five weeks after carcinogen treatment, mice were sacrificed, and the prevalence and multiplicity of liver tumors were determined. Whereas only 1 small liver tumor was observed in 15 AhR-wild-type mice, 19 tumors (two >1 cm in diameter) were present in 18 CA-AhR-transgenic mice. This result demonstrates the oncogenic potential of the activated AhR and implicates an important role of the receptor in promotion of hepatocarcinogenesis. A microarray-based gene expression-profiling analysis revealed down-regulation in the liver of CA-AhR-transgenic mice of a cluster of genes encoding heat shock proteins, including GRP78/BiP, Herp1, Hsp90, DnaJ (Hsp40) homologue B1, and Hsp105, which are important for protein folding and quality control.
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PMID:A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. 1525 35

The production of erythrocytes requires the massive synthesis of red cell-specific proteins including hemoglobin, cytoskeletal proteins, as well as membrane glycoproteins glycophorin A (GPA) and anion exchanger 1 (AE1). We found that during the terminal differentiation of human CD34(+) erythroid progenitor cells in culture, key components of the endoplasmic reticulum (ER) protein translocation (Sec61alpha), glycosylation (OST48), and protein folding machinery, chaperones BiP, calreticulin (CRT), and Hsp90 were maintained to allow efficient red cell glycoprotein biosynthesis. Unexpected was the loss of calnexin (CNX), an ER glycoprotein chaperone, and ERp57, a protein-disulfide isomerase, as well as a major decrease of the cytosolic chaperones, Hsc70 and Hsp70, components normally involved in membrane glycoprotein folding and quality control. AE1 can traffic to the cell surface in mouse embryonic fibroblasts completely deficient in CNX or CRT, whereas disruption of the CNX/CRT-glycoprotein interactions in human K562 cells using castanospermine did not affect the cell-surface levels of endogenous GPA or expressed AE1. These results demonstrate that CNX and ERp57 are not required for major glycoprotein biosynthesis during red cell development, in contrast to their role in glycoprotein folding and quality control in other cells.
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PMID:Loss of specific chaperones involved in membrane glycoprotein biosynthesis during the maturation of human erythroid progenitor cells. 1925 25


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