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)

To understand how the endoplasmic reticulum (ER) of the thyrocyte remains flexible to physiologic changes in the load of exportable proteins, we have examined hormonally-induced increments in thyroglobulin (Tg) flux and pool size in the ER, the relationship between kinetics of Tg folding and ER export, and steady-state levels of molecular chaperones. Tg production was increased > or = 5-fold by chronic exposure to thyrotropin (TSH), and > or = 25-fold by exposure to a mixture of TSH, insulin, transferrin, and hydrocortisone (4H). In TSH-grown cells Tg assembly was accelerated, specifically involving early folding intermediates that lead to a compact monomer. Accelerated dissociation of nascent Tg from the binding protein, BiP, was observed in parallel. TSH exposure was accompanied by modest increases in ER chaperones as well as accelerated Tg export from the thyrocyte ER. However, in 4H-grown thyrocytes, although there were further increases in ER chaperones, monomer maturation was slowed and the association between nascent Tg and BiP was prolonged. Nevertheless, export from the ER remained accelerated, indicating that exit from the ER must include other regulated steps that occur after the folding of exportable proteins. Thus, protein folding may not necessarily be the rate-limiting step in the export of newly synthesized proteins from the ER.
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PMID:Hormonal regulation of thyroglobulin export from the endoplasmic reticulum of cultured thyrocytes. 809 63

PDI catalyzes the formation of disulfide bonds and plays a central role in the correct folding of nascent polypeptides. In addition, it is multifunctional and may participate in more complex enzyme systems, catalyzing other protein modification. PDI is also known to bind T3. The human T3BP/PDI gene, located in the chromosome 17, consists of a transcribed part of 16.5 kb and the protein coding sequence is divided into 11 exons. The analysis of the 5'-flanking region revealed several putative transcriptional elements, including a TATA box, 6 CCAAT elements and 5 GC-rich regions, each of which is related to the promoter activity. The mechanism of T3BP/PDI gene expression is, however, unknown. Treatment with T4, PTU, insulin and fasting-refeeding induced different responses in T3BP/PDI mRNA and protein levels among various tissues. Recent studies revealed that the unfolded proteins, accumulated in the ER lumen, might stimulate the gene expression of a set of protein including BiP, GRp94 and PDI, which is required for proper protein folding and assembling. The meaning of T3-binding activity of PDI is open for further study.
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PMID:[Regulation of thyroid hormone binding protein/protein disulfide isomerase (T3BP/PDI) gene expression]. 819 77

It has been shown previously that CaBP2, the rat analog of the murine protein ERp72, and CaBP1, the rat analogue of the hamster protein P5, represent members of the protein disulfide isomerase (PDI) family and are able to catalyze the reduction of insulin in the presence of various reductants (Nguyen Van et al., 1993). We have now examined the abilities of CaBP2 and CaBP1 to catalyze the renaturation of denatured reduced model proteins. Both CaBP2 and CaBP1 catalyzed the reappearance of the biological activity of the denatured reduced Fab fragment of a monoclonal anti-human creatine phosphokinase antibody. The reaction rate was positively correlated with the amount of CaBP2 or CaBP1 and dependent on the GSH/GSSG ratio (maximum at GSH/GSSG = 1). Peptide prolyl-cis,trans-isomerase (PPI), which catalyzed some renaturation on its own, showed synergistic effects with PDI, CaBP2, and CaBP1. No synergistic effects could be observed when the combinations CaBP2 + PDI, CaBP1 + PDI, or CaBP2 + CaBP1 were tested. Variation of [Ca2+] between 0 and 1 mM did not have any effect on the rate or amount of renaturation catalyzed by CaBP2, CaBP1, or PDI, nor were these parameters affected by the simultaneous presence of BiP or grp94. Both CaBP2 and CaBP1 catalyzed also the renaturation of denatured reduced ribonuclease AIII in a way that depended on the amounts of CaBP2 or CaBP1 and on the redox potential of the redox system used (GSH/GSSG or CSH/CSSC). PPI alone had no effect on the rate of RNase AIII renaturation and did not significantly affect renaturation catalyzed by PDI, CaBP2, or CaBP1. PDI showed a moderate but significant synergism with CaBP2, and a strong synergism with CaBP1. The results indicate that both CaBP2 and CaBP1 can catalyze the formation of disulfide bonds and protein disulfide isomerization and may thus be involved in the folding of nascent proteins in the secretory pathway. This does not exclude the possibility of additional functions of these proteins in the pre-Golgi compartments.
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PMID:Effects of CaBP2, the rat analog of ERp72, and of CaBP1 on the refolding of denatured reduced proteins. Comparison with protein disulfide isomerase. 830 May 76

We have examined the binding specificities of Hsp70 family molecular chaperones, BiP and Hsp70/Hsc70, to wild-type or mutant insulin receptors. BiP bound to proreceptor of wild-type insulin receptor, but not to mature receptor. A mutant insulin receptor, which lacked 47 amino acid residues (delta Ex13 IR) corresponding to exon 13 of insulin receptor gene, accumulated in the endoplasmic reticulum as uncleaved proreceptor with immature oligosaccharide chains. This deletion mutant bound to BiP more tightly than wild type. Introduction of two types of mutations, Asp1179 or Leu1193, into delta Ex13 IR led to accelerated degradation, and these double mutants bound weakly to BiP. In contrast, Ser735 insulin receptor was normally transported to the plasma membrane and normally bound to BiP. Furthermore, Asp1179, Leu1193 insulin receptors and delta Ex13 IR combination mutant with either Asp1179 or Leu1193 bound more tightly to Hsp70/Hsc70 compared with wild-type, Ser735, and delta Ex13 IR. These results suggest that the binding specificity of mutant insulin receptors to two molecular chaperones, i.e., BiP and Hsp70/Hsc70, plays an important role for their posttranslational processing that may lead to the accumulation in the endoplasmic reticulum or the degradation of insulin receptors.
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PMID:Hsp70 family molecular chaperones and mutant insulin receptor: differential binding specificities of BiP and Hsp70/Hsc70 determines accumulation or degradation of insulin receptor. 856 76

The 78 kDa glucose-regulated protein (grp78) is an abundant member of the 70 kDa molecular chaperone family in the lumen of the endoplasmic reticulum participating in the quality control of secretory proteins. In the present paper we have analysed the synthesis and level of grp78 in livers of control, streptozotocin-diabetic, and the spontaneously diabetic Zucker rats. The level of grp78 mRNA significantly decreased in streptozotocin-diabetic rats. The effect was reversed by insulin treatment. In case of Zucker rats we did not detect any significant change in grp78 mRNA, grp78 protein level showed opposite changes being essentially unchanged in streptozotocin-diabetes and significantly reduced in Zucker rats. Autoradiograms of Ca-dependent phosphorylation of postmitochondrial supernatants of control and streptozotocin-diabetic livers indicated no significant changes in the 70 kDa region. Decrease in the availability of grp78 may participate in the attenuation of hepatic protein secretion in diabetes.
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PMID:Changes of the 78 kDa glucose-regulated protein (grp78) in livers of diabetic rats. 886 96

The mouse autosomal dominant mutation Mody develops hyperglycemia with notable pancreatic beta-cell dysfunction. This study demonstrates that one of the alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form. This mutation disrupts a disulfide bond between the A and B chains and can induce a drastic conformational change of this molecule. Although there was no gross defect in the transcription from the wild-type insulin 2 allele or two alleles of insulin 1, levels of proinsulin and insulin were profoundly diminished in the beta cells of Mody mice, suggesting that the number of wild-type (pro)insulin molecules was also decreased. Electron microscopy revealed a dramatic reduction of secretory granules and a remarkably enlarged lumen of the endoplasmic reticulum. Little proinsulin was processed to insulin, but high molecular weight forms of proinsulin existed with concomitant overexpression of BiP, a molecular chaperone in the endoplasmic reticulum. Furthermore, mutant proinsulin expressed in Chinese hamster ovary cells was inefficiently secreted, and its intracellular fraction formed complexes with BiP and was eventually degraded. These findings indicate that mutant proinsulin was trapped and accumulated in the endoplasmic reticulum, which could induce beta-cell dysfunction and account for the dominant phenotype of this mutation.
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PMID:A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. 988 31

Glucose deprivation leads to the synthesis of an aberrantly glycosylated ('alternative') and inefficiently processed form of the insulin proreceptor in 3T3-L1 adipocytes. To further explore the effect of aberrant (rather than absent) N-linked glycosylation of the insulin receptor, we examined the relationship of processing to function. Our studies show that the alternative form of the proreceptor does not oligomerize nor does it acquire the ability to undergo insulin-sensitive autophosphorylation. This along with an interaction with the glucose-regulated stress protein GRP78/BiP implies inappropriate folding/dimerization and retention in the ER. Glucose refeeding causes the post-translational modification of the alternative form of the proreceptor to a novel 'intermediate' form which is independent of new protein synthesis. As little as 100 microM glucose (or mannose) can induce this modification. In vitro digestion of the alternative and intermediate proreceptors with SPC1/furin shows that both the alpha- and beta-subunit domains are glycosylated, albeit aberrantly. This implies that the aberrantly glycosylated proreceptor could serve as a substrate for SPC1 in a physiological setting if the receptor was able to interact with the enzyme in the appropriate compartment (i.e., the trans-Golgi network). Based on inhibitor studies, however, both the alternative and intermediate forms of the proreceptor appear to be primarily targeted to the proteasome for degradation.
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PMID:Alternative glycosylation of the insulin receptor prevents oligomerization and acquisition of insulin-dependent tyrosine kinase activity. 1111 40

Myoblasts transfected with HB10D insulin secrete more hormone than those transfected with wild-type insulin, as published previously, indicating that production of wild-type insulin is not efficient in these cells. The ability of non-beta-cells to produce insulin was examined in several cell lines. In clones of neuroendocrine GH(4)C(1) cells stably transfected with proinsulin, two thirds of (35)S-proinsulin was degraded within 3 h of synthesis, whereas (35)S-prolactin was stable. In transiently transfected neuroendocrine AtT20 cells, half of (35)S-proinsulin was degraded within 3 h after synthesis, whereas (35)S-GH was stable. In transiently transfected fibroblast COS cells, (35)S-proinsulin was stable for longer, but less than 10% was secreted 8 h after synthesis. Proinsulin formed a concentrated patch detected by immunofluorescence in transfected cells that did not colocalize with calreticulin or BiP, markers for the endoplasmic reticulum, but did colocalize with membrin, a marker for the cis-medial Golgi complex. Proinsulin formed a Lubrol-insoluble aggregate within 30 min after synthesis in non-beta-cells but not in INS-1E cells, a beta-cell line that normally produces insulin. More than 45% of (35)S-HB10D proinsulin was secreted from COS cells 3 h after synthesis, and this mutant formed less Lubrol-insoluble aggregate in the cells than did wild-type hormone. These results indicate that proinsulin production from these non-beta-cells is not efficient and that proinsulin aggregates in their secretory pathways. Factors in the environment of the secretory pathway of beta-cells may prevent aggregation of proinsulin to allow efficient production.
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PMID:Aggregation and lack of secretion of most newly synthesized proinsulin in non-beta-cell lines. 1511 81

Metabolic labeling studies were conducted in freshly isolated mouse islets and a beta-cell line (MIN6) to examine the effects of proteasome inhibition on glucose-stimulated (pro)insulin synthesis and secretion. Glucose-stimulated (pro)insulin synthesis, as determined by the incorporation of [(3)H]tyrosine, decreased significantly by 90% in islets and 71% in MIN6 cells pretreated with the proteasome inhibitor lactacystin (10 microM) for 2 h. To follow the fate of newly synthesized (pro)insulin, islets were pulse-labeled with [(3)H]tyrosine (40 microCi) for 20 min and chased +/- lactacystin (10 microM) for up to 4 h. The release of newly synthesized (pro)insulin ([(3)H]tyrosine-labeled) was similar between lactacystin-treated and control islets despite a 51% decrease (p <0.05) in total immunoreactive (pro)insulin secretion by lactacystin-treated islets. The specific radioactivity of [(3)H]tyrosine-labeled (pro)insulin in the extracellular medium of lactacystin-treated islets (0.52 +/- 0.16 cpm/microunits) was 2-fold greater relative to control islets (0.25 +/- 0.06 cpm/microunits). Induction of the unfolded protein response by lactacystin, as evidenced by the up-regulation of endoplasmic reticulum (ER) chaperones (GRP78/BiP, GRP94, protein disulfide isomerase) and induction of the stress-inducible transcription factor C/EBP-homologous protein/GADD153 (CHOP/GADD153), likely contributed to the release of newly synthesized (pro)insulin to relieve ER stress. The present data indicate proteasome inhibition did not prevent, but increased (p <0.05), the intracellular degradation of [(3)H]tyrosine-labeled (pro-)insulin from 8 to 24% in islets. Collectively, these data indicate beta-cells may balance glucose-stimulated (pro)insulin synthesis and secretion with the activity of the proteasome to regulate protein concentrations in the ER.
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PMID:Proteasome inhibition alters glucose-stimulated (pro)insulin secretion and turnover in pancreatic {beta}-cells. 1570 91

In pancreatic beta cells, the endoplasmic reticulum (ER) is an important site for insulin biosynthesis and the folding of newly synthesized proinsulin. Here, we show that IRE1alpha, an ER-resident protein kinase, has a crucial function in insulin biosynthesis. IRE1alpha phosphorylation is coupled to insulin biosynthesis in response to transient exposure to high glucose; inactivation of IRE1alpha signaling by siRNA or inhibition of IRE1alpha phosphorylation hinders insulin biosynthesis. IRE1 activation by high glucose does not accompany XBP-1 splicing and BiP dissociation but upregulates its target genes such as WFS1. Thus, IRE1 signaling activated by transient exposure to high glucose uses a unique subset of downstream components and has a beneficial effect on pancreatic beta cells. In contrast, chronic exposure of beta cells to high glucose causes ER stress and hyperactivation of IRE1, leading to the suppression of insulin gene expression. IRE1 signaling is therefore a potential target for therapeutic regulation of insulin biosynthesis.
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PMID:Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. 1695 Jan 32


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