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

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.
 ...
PMID:Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. 1695 Jan 32

Mammalian transcription factor ATF6 is constitutively synthesized as a type II transmembrane protein embedded in the endoplasmic reticulum (ER). It is activated when unfolded proteins are accumulated in the ER under ER stress through a process called regulated intramembrane proteolysis (Rip), in which ATF6 is transported from the ER to the Golgi apparatus where it undergoes sequential cleavage by Site-1 and Site-2 proteases. The cytosolic transcription factor domain of ATF6 liberated from the Golgi membrane enters the nucleus where it activates transcription of ER-localized molecular chaperones and folding enzymes, leading to the maintenance of the homeostasis of the ER. Here, we analyzed M19 cells, a mutant of Chinese hamster ovary cells deficient in Site-2 protease. It was previously shown that M19 cells are defective in the induction of mRNA encoding the major ER chaperone BiP. In M19 cells, ATF6 was not converted from the membrane-bound precursor form to the cleaved and nuclear form as expected. Moreover, some of the ATF6 was constitutively relocated to the Golgi apparatus, where it was cleaved by Site-1 protease, and remained associated with the Golgi apparatus, indicating that the ER of M19 cells was constitutively stressed. Consistent with this notion, the two other ER stress response mediators, IRE1 and PERK, were also constitutively activated in M19 cells. M19 cells showed inefficient secretion of a model protein. These results suggest that Rip-mediated activation of ATF6 is important for the homeostasis of the ER in not only ER-stressed but also unstressed cells.
 ...
PMID:Analysis of ATF6 activation in Site-2 protease-deficient Chinese hamster ovary cells. 1711 Jul 86

Plasma cells producing high levels of paraprotein are dependent on the unfolded protein response (UPR) and chaperone proteins to ensure correct protein folding and cell survival. We hypothesized that disrupting client-chaperone interactions using heat shock protein 90 (Hsp90) inhibitors would result in an inability to handle immunoglobulin production with the induction of the UPR and myeloma cell death. To study this, myeloma cells were treated with Hsp90 inhibitors as well as known endoplasmic reticulum stress inducers and proteasome inhibitors. Treatment with thapsigargin and tunicamycin led to the activation of all 3 branches of the UPR, with early splicing of XBP1 indicative of IRE1 activation, upregulation of CHOP consistent with ER resident kinase (PERK) activation, and activating transcription factor 6 (ATF6) splicing. 17-AAG and radicicol also induced splicing of XBP1, with the induction of CHOP and activation of ATF6, whereas bortezomib resulted in the induction of CHOP and activation of ATF6 with minimal effects on XBP1. After treatment with all drugs, expression levels of the molecular chaperones BiP and GRP94 were increased. All drugs inhibited proliferation and induced cell death with activation of JNK and caspase cleavage. In conclusion, Hsp90 inhibitors induce myeloma cell death at least in part via endoplasmic reticulum stress and the UPR death pathway.
 ...
PMID:Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. 1752 89

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the ER membrane kinases PERK and IRE1 leading to the unfolded protein response (UPR). We show here that UPR activation triggers PERK and IRE1 segregation from BiP and their sorting with misfolded proteins to the ER-derived quality control compartment (ERQC), a pericentriolar compartment that we had identified previously. PERK phosphorylates translation factor eIF2alpha, which then accumulates on the cytosolic side of the ERQC. Dominant negative PERK or eIF2alpha(S51A) mutants prevent the compartmentalization, whereas eIF2alpha(S51D) mutant, which mimics constitutive phosphorylation, promotes it. This suggests a feedback loop where eIF2alpha phosphorylation causes pericentriolar concentration at the ERQC, which in turn amplifies the UPR. ER-associated degradation (ERAD) is an UPR-dependent process; we also find that ERAD components (Sec61beta, HRD1, p97/VCP, ubiquitin) are recruited to the ERQC, making it a likely site for retrotranslocation. In addition, we show that autophagy, suggested to play a role in elimination of aggregated proteins, is unrelated to protein accumulation in the ERQC.
 ...
PMID:PERK-dependent compartmentalization of ERAD and unfolded protein response machineries during ER stress. 1770 96

Cigarette smoke (CS) generally places severe stress on cells, as reflected by gene expression profiling and pathway analysis, which, among other effects, also suggested activation of the unfolded protein response pathway triggered by the stressed endoplasmic reticulum (ER stress). Here, we present data indicating that noncytotoxic concentrations of aqueous extracts of CS induce a distinct ER stress response in immortalized nontransformed Swiss 3T3 cells, primarily by activating the PERK pathway of global protein synthesis inhibition. Activation of PERK and PERK-dependent signaling by aqueous extracts of CS was demonstrated by (i) the inhibition of protein synthesis, (ii) the phosphorylation of PERK and its substrate eIF2alpha, (iii) the activation of ATF4, and (iv) the expression of ATF4-dependent target genes chop, gadd34, BiP, and atf3. Within the dose range tested, all effects appeared to be transient in nature, while the periods of recovery from ER stress were clearly concentration dependent. In contrast to these data and to the effects seen with thapsigargin (used as positive control), only minor effects were observed for the activation of xbp-1, a common target of the other two canonical sensors of ER stress, i.e., ATF6 and IRE1. In mechanistic terms, neither the disruption of energy levels nor a contribution of arylating quinones played a major role under the experimental conditions tested. Notably however, the effects of aqueous extracts of CS on the ER could be mimicked in the presence of acrolein at CS-relevant concentrations, indicating that CS interferes with proper ER function, presumably due mainly to changes in cellular redox homeostasis. Since ER stress has been linked to diseases that are also related to CS exposure, these data are relevant in the discussion of a general molecular mechanism of CS-induced disease.
 ...
PMID:Endoplasmic reticulum stress induced by aqueous extracts of cigarette smoke in 3T3 cells activates the unfolded-protein-response-dependent PERK pathway of cell survival. 1820 57

Disruption of endoplasmic reticulum (ER) homeostasis causes accumulation of unfolded and misfolded proteins in the ER, triggering the ER stress response, which can eventually lead to apoptosis when ER dysfunction is severe or prolonged. Here we demonstrate that human MCF-7 breast cancer cells, as well as murine NIH/3T3 fibroblasts, are rescued from ER stress-initiated apoptosis by insulin-like growth factor-I (IGF-I). IGF-I significantly augments the adaptive capacity of the ER by enhancing compensatory mechanisms such as the IRE1 alpha-, PERK- and ATF6-mediated arms of ER stress signalling. During ER stress, IGF-I stimulates translational recovery and induces expression of the key molecular chaperone protein Grp78/BiP, thereby enhancing the folding capacity of the ER and promoting recovery from ER stress. We also demonstrate that the antiapoptotic activity of IGF-I during ER stress may be mediated by a novel, as yet unidentified, signalling pathway(s). Application of signal transduction inhibitors of MEK (U1026), PI3K (LY294002 and wortmannin), JNK (SP600125), p38 (SB203580), protein kinases A and C (H-89 and staurosporine) and STAT3 (Stattic) does not prevent IGF-I-mediated protection from ER stress-induced apoptosis. Taken together, these data demonstrate that IGF-I protects against ER stress-induced apoptosis by increasing adaptive mechanisms through enhancement of ER stress-signalling pathways, thereby restoring ER homeostasis and preventing apoptosis.
 ...
PMID:Insulin-like growth factor-I protects cells from ER stress-induced apoptosis via enhancement of the adaptive capacity of endoplasmic reticulum. 1843 63

Calnexin is a type I integral endoplasmic reticulum (ER) membrane chaperone involved in folding of newly synthesized (glycol)proteins. In this study, we used beta-galactosidase reporter gene knock-in and reverse transcriptase polymerase chain reaction (RT-PCR) to investigate activation of the calnexin gene during embryonic development. We showed that the calnexin gene was activated in neuronal tissue at the early stages of embryonic development but remained low in the heart, intestine, and smooth muscle. At early stages of embryonic development, large quantities of calnexin messenger RNA (mRNA) were also found in neuronal tissue and liver. There was no detectable calnexin mRNA in the heart, lung, and intestine. The absence of calnexin had no significant effect on ER stress response (unfolded protein response, UPR) at the tissue level as tested by IRE1-dependent splicing of Xbp1 mRNA. In contrast, non-stimulated calnexin-deficient cells showed increased activation of IRE1, as measured by RT-PCR and luciferase reporter gene analysis of splicing of Xbp1 mRNA and activation of the BiP promoter. This indicates that cnx (-/-) cells have increased constitutively active UPR. Importantly, cnx (-/-) cells have significantly increased proteasomal activity, which may play a role in the adaptive mechanisms addressing the acute ER stress observed in the absence of calnexin.
 ...
PMID:Endoplasmic reticulum stress in the absence of calnexin. 1852 84

The effects of La3+ on the unfolded protein response signaling pathways were investigated in human hepatoblastoma HepG2 cells. Our data showed that La3+ could induce unfolded protein response in HepG2 cells, including a significant increase of BiP/GRP78 level, which is an important ER residential chaperone and an ER stress hallmark, in a concentration and time-dependent manner, UPR transducer IRE1 phosphorylation and splicing activation IRE1 downstream substrate XBP1 mRNA. By using La3+-affinity chromatography, the possible cellular target of La3+ leading to UPR events was shown to be the ER residential chaperone BiP/GRP78. BiP/GRP78 was shown to be a La3+ binding protein and the interaction of La3+ with BiP/GRP78 resulted in dissociation of BiP-IRE1 complexes. La3+ induced dissociation of the BiP/GRP78-IRE1 complex was in a time and concentration manner. The apparent dissociation constant was estimated to be 4 nM. In addition, La3+ was observed to slightly stimulate the production of cellular ROS and cause alteration of intracellular Ca2+, indicating the possible involvement of ROS and Ca2+ alteration in La3+ induced UPR. The present work provides a new perspective for understanding the biological and toxicological effects of La3+.
 ...
PMID:La3+ binds to BiP/GRP78 and induces unfolded protein response in HepG2 cells. 1877 83

Oxidative stress and endoplasmic reticulum (ER) stress have been implicated in cardiovascular diseases although the interplay between the two is not clear. This study was designed to examine the influence of oxidative stress through glutathione depletion on myocardial ER stress and contractile function in the absence or presence of the heavy metal scavenger antioxidant metallothionein (MT). FVB and MT overexpression transgenic mice received the GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mM) in drinking water for 2 weeks. Oxidative stress, ER stress, apoptosis, cardiac function and ultrastructure were assessed using GSH/GSSG assay, reactive oxygen species (ROS), immunoblotting, caspase-3 activity, Langendorff perfused heart function (LVDP and +/-dP/dt), and transmission electron microscopy. BSO led to a robust decrease in the GSH/GSSG ratio and increased ROS production, consolidating oxidative stress. Cardiac function and ultrastructure were compromised following BSO treatment, the effect of which was obliterated by MT. BSO promoted overt ER stress as evidenced by upregulated BiP, calregulin, phospho-IRE1 alpha and phospho-eIF2 alpha without affecting total IRE1 alpha and eIF2 alpha. BSO treatment led to apoptosis manifested as elevated expression of CHOP/GADD153, caspase-12 and Bax as well as caspase-3 activity, reduced Bcl-2 expression and JNK phosphorylation, all of which was ablated by MT. Moreover, both antioxidant N-acetylcysteine and the ER stress inhibitor tauroursodeoxycholic acid reversed the oxidative stress inducer menadione-elicited depression in cardiomyocyte contractile function. Taken together, these data suggested that ER stress occurs likely downstream of oxidative stress en route to cardiac dysfunction.
 ...
PMID:Metallothionein alleviates oxidative stress-induced endoplasmic reticulum stress and myocardial dysfunction. 1934 29

IRE1, an ER-localized transmembrane protein, plays a central role in the unfolded protein response. Upon ER stress, IRE1 senses the accumulation of unfolded proteins in the ER, and transfers signal from the ER to the cytosol. Recently, it was reported that the luminal domain of yeast Ire1 senses the unfolded proteins via a two-step mechanism, namely dissociation of BiP and direct interaction with unfolded proteins. However, it has been unclear whether a similar mechanism is applicable to mammalian IRE1alpha. To address this point, we analyzed luminal-domain mutants of mammalian IRE1alpha in cells, and evaluated the anti-aggregation activity of the luminal fragment of IRE1alpha in vitro. We generated a mutant that has low affinity for BiP, and this mutant was significantly activated even under normal conditions. Moreover, the luminal fragments of mammalian IRE1alpha did not exhibit anti-aggregation activity. These results suggest that in contrast to yeast Ire1, the regulation of mammalian IRE1alpha strongly depends on the dissociation of BiP.
 ...
PMID:Activation of mammalian IRE1alpha upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins. 1953 57


<< Previous 1 2 3 4 5 6 7 8 9 Next >>