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)

Previous studies on the fate of human thyroperoxidase (hTPO) molecules have shown that, after being synthesized, these glycoproteins interact with calnexin and calreticulin and that only some of them are able to acquire a partially folded structure. The aim of the present study was to further investigate the potential role of BiP, another major protein chaperon. Co-immunoprecipitation experiments showed the occurrence of interactions between hTPO and BiP. Pulse-chase studies showed that, when hTPO was expressed in a Chinese hamster ovary cell line overexpressing 5 times more BiP than the parent cells, the rate of hTPO recognized by a monoclonal antibody directed against a conformational structure decreased by 50% after 5 h of chase. Overexpression of the BiP-ATPase mutant G37T also led to a decrease in the correct folding rate of hTPO. When this protein was pulsed in the presence of 35S-(Met + Cys) and the reducing agent dithiotreitol and then chased in a culture medium without dithiothreitol, a 2.5-fold decrease in the correct folding rate was observed in cells overexpressing BiP, whereas co-overexpression of calnexin and Erp57 led to an increase in both the unfolded and partially folded form of hTPO after the pulse step. All of these findings show that BiP and calnexin have opposite effects on the folding behavior of hTPO and that the action of specific molecular chaperones may therefore crucially determine the fate of glycoproteins.
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PMID:Competition between calnexin and BiP in the endoplasmic reticulum can lead to the folding or degradation of human thyroperoxidase. 1675 27

To explore the function of endoplasmic reticulum-located small heat-shock proteins (ER-sHSPs) in ER stress, a putative ER-sHSP cDNA (the driven protein was named as LeHSP21.5 with GenBank accession No. AB026983) was isolated from tomato (Lycopersicon esculentum). Fractionation of the crude microsomes by isopycnic sucrose-gradient centrifugation revealed that LeHSP21.5 was distributed on a density corresponding to the fractions with a higher activity of ER marker enzyme, suggesting the localization of LeHSP21.5 in the ER. Overexpressing LeHSP21.5 in transgenic tomato plants (L. esculentum var. Zhongshu 4) greatly attenuated the lethal effect of tunicamycin on tomato seedlings. Moreover, under the tunicamycin treatment, transcripts of BiP, PDI and calnexin in transgenic tomato plants accumulated to a less level than those in non-transgenic tomato plants. These results suggest that LeHSP21.5 can function to alleviate the tunicamycin-induced ER stress.
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PMID:Constitutive expression of an endoplasmic reticulum small heat shock protein alleviates endoplasmic reticulum stress in transgenic tomato. 1690 32

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen causes ER stress response in eukaryote cells, activates the unfolded protein response (UPR) and consequently induces the expression of ER-located molecular chaperones (such as BiP, calnexin, etc.). In this study, the full-length small heat-shock protein of endoplasmic reticulum cDNA (ER-sHSP) under the control of CaMV 35S promoter was introduced into tomato by Agrobacterium tumefactions mediated method (Fig. 1, Table 1). Overexpression of ER-sHSP enhanced the resistance of the transgenic plant to tunicamycin (Fig. 2, Table 2), an inducer of ER stress. Tunicamycin treatment induced an increase in mRNA level of BiP and calnexin in plant cell, but mRNAs of these two genes in transgenic plants were accumulated to a much smaller extent than those in non-transgenic plants (Fig. 3). These results indicated that ER-sHSP could alleviate the ER stress and may be involved in the UPR signal transmission pathway.
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PMID:[Overexpression of small heat-shock protein of endoplasmic reticulum enhances resistance of tomato to tunicamycin]. 1695 93

Protein secretion is a complex process that can be modulated by folding factors in the endoplasmic reticulum (ER), such as calnexin, a highly-conserved molecular chaperone involved in quality control. In Schizosaccharomyces pombe, calnexin (Cnx1p) is essential for cell viability. The calnexin/Cnx1p determinants required for viability have been mapped within the last 123 residues of its C-terminus. To better understand the role(s) of calnexin/Cnx1p in secretion, we screened for cnx1 mutants 'super-secreting' cellulase. We identified ss14_cnx1, a mutant secreting 10-fold higher levels of the glycoprotein cellulase than the wild-type strain. While cellulase did not interact with ss14_Cnx1p, the ratio of secreted activity/quantity for this enzyme was not affected, suggesting that the quality control of folding in the ER was adequate in the mutant strain. Surprisingly, the ss14_Cnx1p mutant is composed of the 160 N-terminal amino acids of the mature molecule, thus this mutant defines a novel calnexin/Cnx1p region supporting Sz. pombe viability. Interestingly, like viable mutants spanning the last 52 aa of calnexin/Cnx1p, the 160 N-terminal residues encoded by ss14_cnx1 also forms a complex with the essential BiP chaperone. These results reveal the so far unidentified importance of the N-terminal region of calnexin/Cnx1p.
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PMID:The 160 N-terminal residues of calnexin define a novel region supporting viability in Schizosaccharomyces pombe. 1723 May 81

Bortezomib (Velcade) exploits proteasome inhibition as a unique mechanism of anticancer activity. The effectiveness of bortezomib is, however, limited, therefore, the search for therapeutic regimens combining bortezomib with other agents. In the present work we demonstrate enhanced anticancer activity of bortezomib by its combination with tumor necrosis factor (TNF) in the experimental model of C-26 colon carcinoma in mice. This interaction likely relies on the induction of a dysregulated response to ER stress, leading to apoptosis of cancer cells, evidenced by caspase-3 cleavage, p53 accumulation as well as increased SAPK/JNK phosphorylation. ER stress induced by the combination of TNF and bortezomib is corroborated by upregulation of BiP, PDI and calnexin as well as cleavage of caspase-12; however, in contrast to the classic pathway, it is also associated with decreased phosphorylation of eIF2 alpha and prevention of XBP-1 splicing. TNF prevented the upregulation of Hsp27 induced by bortezomib, which may contribute to enhanced ER stress. Moreover, TNF interfered with bortezomib-induced upregulation of distinct subunits of the 26S proteasome. Bortezomib concentration used in this study was not sufficient to prevent TNF from inducing nuclear translocation of p65/RelA; however, the combination of both agents reduced total p65/RelA levels. Combined treatment of tumor-bearing mice with bortezomib and TNF not only inhibited tumor growth but also significantly prolonged animal survival. Therefore, combination of bortezomib with TNF is an attractive option for further clinical studies.
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PMID:TNF potentiates anticancer activity of bortezomib (Velcade) through reduced expression of proteasome subunits and dysregulation of unfolded protein response. 1737 61

The field of endoplasmic reticulum (ER) stress in mammalian cells has expanded rapidly during the past decade, contributing to understanding of the molecular pathways that allow cells to adapt to perturbations in ER homeostasis. One major mechanism is mediated by molecular ER chaperones which are critical not only for quality control of proteins processed in the ER, but also for regulation of ER signaling in response to ER stress. Here, we summarized the properties and functions of GRP78/BiP, GRP94/gp96, GRP170/ORP150, GRP58/ERp57, PDI, ERp72, calnexin, calreticulin, EDEM, Herp and co-chaperones SIL1 and P58(IPK) and their role in development and diseases. Many of the new insights are derived from recently constructed mouse models where the genes encoding the chaperones are genetically altered, providing invaluable tools for examining the physiological involvement of the ER chaperones in vivo.
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PMID:ER chaperones in mammalian development and human diseases. 1748 12

Glycoprotein folding is mediated by lectin-like chaperones and protein disulfide isomerases (PDIs) in the endoplasmic reticulum. Calnexin and the PDI homologue ERp57 work together to help fold nascent polypeptides with glycans located toward the N-terminus of a protein, whereas PDI and BiP may engage proteins that lack glycans or have sugars toward the C-terminus. In this study, we show that the PDI homologue PDILT is expressed exclusively in postmeiotic male germ cells, in contrast to the ubiquitous expression of many other PDI family members in the testis. PDILT is induced during puberty and represents the first example of a PDI family member under developmental control. We find that PDILT is not active as an oxido-reductase, but interacts with the model peptide Delta-somatostatin and nonnative bovine pancreatic trypsin inhibitor in vitro, indicative of chaperone activity. In vivo, PDILT forms a tissue-specific chaperone complex with the calnexin homologue calmegin. The identification of a redox-inactive chaperone partnership defines a new system of testis-specific protein folding with implications for male fertility.
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PMID:A developmentally regulated chaperone complex for the endoplasmic reticulum of male haploid germ cells. 1750 49

Recently, it was shown that glycoproteins with N-glycans close to the NH(2) terminus can directly enter the calnexin/calreticulin cycle and bypass BiP binding. This should allow efficient secretion of glycoproteins such as factor VIII (FVIII) whose secretion is negatively affected by BiP interaction. Examination of the glycosylation pattern of the NH(2) terminus of FV and FVIII revealed N-glycans at positions 23 and 27 in FV and at position 41 in FVIII. To improve FVIII secretion, a 14-amino-acid-long polypeptide with (G3) or without (G0; control) three N-linked glycosylation consensus sites was inserted upstream of the NH(2) terminus of a B-domain deleted FVIII protein. Expression of G3- and G0-constructs in three different cell lines resulted in the same or even higher expression rate of protein as found for the B-domain deleted FVIII. However, as demonstrated by Western blot analysis, the G3- as well as the G0-protein variants were mainly retained inside the cells in similar amounts. Thus, glycosylation alone does not automatically lead to higher secretion rates, but must be in context to the normal structure of the FVIII protein.
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PMID:Modified expression of coagulation factor VIII by addition of a glycosylation site at the N terminus of the protein. 1789 80

It has been suggested that a thyroglobulin (Tg)-R19K missense mutation may be a newly identified cause of human congenital goiter, which is surprising for this seemingly conservative substitution. Here, we have examined the intracellular fate of recombinant mutant Tg expressed in COS-7 cells. Incorporation of the R19K mutation largely blocked Tg secretion, and this mutant was approximately 90% degraded intracellularly over a 24-h period after synthesis. Before its degradation, the Tg-R19K mutant exhibited abnormally increased association with molecular chaperones BiP, calnexin, and protein disulfide isomerase, and was unable to undergo anterograde advance from the endoplasmic reticulum (ER) through the Golgi complex. Inhibitors of proteasomal proteolysis and ER mannosidase-I both prevented ER-associated degradation of the Tg-R19K mutant and increased its association with ER molecular chaperones. ER quality control around Tg residue 19 is not dependent upon charge but upon side-chain packing, because Tg-R19Q was efficiently secreted. Whereas a Tg mutant truncated after residue 174 folds sufficiently well to escape ER quality control, introduction of the R19K point mutation blocked its secretion. The data indicate that the R19K mutation induces local misfolding in the amino-terminal domain of Tg that has global effects on Tg transport and thyroid hormonogenesis.
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PMID:Defective protein folding and intracellular retention of thyroglobulin-R19K mutant as a cause of human congenital goiter. 1791 55

To investigate the disposal of nonglycosylated BiP substrates, we used a nonsecreted kappa LC, which exists in partially (ox1) and completely (ox2) oxidized states. The ox2 form is partially reduced in order to be degraded, and only the ox1 form is ubiquitinated and associates with both Herp and Derlin-1. Herp is in a complex with ubiquitinated proteins and with the 26S proteasome, suggesting that it plays a role in linking substrates with the proteasome. Overexpressed Herp also interacts with two other BiP substrates, but not with two calnexin substrates. Either expression of p97 or Hrd1 mutants, which are in a complex with Herp and Derlin-1, or reduction of Herp levels inhibited the degradation of the BiP substrates, whereas the latter had no effect on the degradation of the calnexin substrates. This result suggests that there is some distinction in the pathways used to dispose of these two types of ERAD substrates.
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PMID:Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp. 1804 51


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