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)

Genes associated with Parkinson's disease (PD) have suggested a role for ubiquitin-proteasome dysfunction and aberrant protein degradation in this disorder. Inasmuch as oxidative stress has also been implicated in PD, the present study examined transcriptional changes mediated by the Parkinsonism-inducing neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+) in a dopaminergic cell line. Microarray analysis of RNA isolated from toxin treated samples revealed that the stress-induced transcription factor CHOP/Gadd153 was dramatically up-regulated by both 6-OHDA and MPP+. Treatment with 6-OHDA also induced a large number of genes involved in endoplasmic reticulum stress and unfolded protein response (UPR) such as ER chaperones and elements of the ubiquitin-proteasome system. Reverse transcription-PCR, Western blotting, and immunocytochemical approaches were used to quantify and temporally order the UPR pathways involved in neurotoxin-induced cell death. 6-OHDA, but not MPP+, significantly increased hallmarks of UPR such as BiP, c-Jun, and processed Xbp1 mRNA. Both toxins increased the phosphorylation of UPR proteins, PERK and eIF2 alpha, but only 6-OHDA increased phosphorylation of c-Jun. Thus, 6-OHDA is capable of triggering multiple pathways associated with UPR, whereas MPP+ exhibits a more restricted response. The involvement of UPR in these widely used neurotoxin models supports the role of ubiquitin-proteasome pathway dysfunction in PD.
 ...
PMID:Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. 1259 33

Mammalian cells respond to endoplasmic reticulum (ER) stress by attenuation of protein translation mediated through the PERK-eIF2alpha pathway and transcriptional activation of genes such as Grp78/BiP encoding ER chaperone proteins. The disruption of PERK function or the blocking of eIF2alpha Ser51 phosphorylation fails to attenuate translation after ER stress and also results in substantial impairment of Grp78/BiP induction by ER stress. While the activation of the Grp78 promoter by the ATF6 pathway through the endoplasmic reticulum stress elements (ERSEs) is well documented, the molecular mechanism linking PERK activation to Grp78 stress induction is unknown. We report here that ATF4, a transcription factor whose translation is up-regulated by the PERK-eIF2alpha pathway, can activate the Grp78 promoter independent of the ERSE. The ATF4-activating site is localized to an ATF/CRE sequence upstream of the ERSEs and is distinct from the C/EBP-ATF composite site previously identified as the ATF4 binding site in the ER stress-inducible chop promoter. In vitro translated ATF4 binding to the ATF/CRE site requires other nuclear co-factors from non-stressed cells, forming a complex that exhibits identical electrophoretic mobility as a thapsigargin-stress induced complex. Here we have identified the closely related ATF1 and CREB1 as nuclear co-factors that form in vivo complexes with endogenous ATF4. ER stress induces CREB1 phosphorylation and ATF1/CREB1 binding to the Grp78 promoter. Through the use of adenoviral vector expression systems, we provide evidence that when ATF4 function is suppressed and its binding partners are not able to compensate for its function, Grp78 induction by Tg and Tu is partially inhibited. Our studies resolve a mechanism responsible for inhibition of Grp78 mRNA induction by ER stress in cells that are functionally null for PERK or devoid of eIF2alpha phosphorylation.
 ...
PMID:Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. 1287 76

The mammalian unfolded protein response (UPR) includes two major branches: one(s) specific to ER stress (Ire1/XBP-1 and ATF6-dependent), and one(s) shared by other cellular stresses (PERK/eIF-2alpha phosphorylation-dependent). Here, we demonstrate that the ER-localized protein Herp represents a second target, in addition to CHOP, that is dually regulated by both the shared and the ER stress-specific branches during UPR activation. For the first time, we are able to assess the contribution of each branch of the UPR in the induction of these targets. We demonstrate that activation of the shared branch of the UPR alone was sufficient to induce Herp and CHOP. ATF4 was not required during ER stress when both branches were used but did contribute significantly to their induction. Conversely, stresses that activated only the shared branch of the UPR were completely dependent on ATF4 for CHOP and Herp induction. Thus, the shared and the ER stress-specific branches of the UPR diverge to regulate two groups of targets, one that is ATF6 and Ire1/XBP-1-dependent, which includes BiP and XBP-1, and another that is eIF-2alpha kinase-dependent, which includes ATF4 and GADD34. The two branches also converge to maximally up-regulate targets like Herp and CHOP. Finally, our studies reveal that a PERK-dependent target other than ATF4 is contributing to the cross-talk between the two branches of the UPR that has previously been demonstrated.
 ...
PMID:Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways. 1474 29

Recent studies have suggested that neuronal death in Alzheimer's disease (AD) or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Inhibition of protein glycosylation, perturbation of calcium homeostasis, and reduction of disulfide bonds provoke accumulation of unfolded protein in the ER, and are called 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, to facilitate protein folding or by suppressing the mRNA translation to synthesize proteins. These systems are termed the unfolded protein response (UPR). 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. On the other hand, in sporadic Alzheimer's disease (sAD), we found the aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, responsible for induction of high mobility group A1a protein (HMGA1a). The PS2V also downregulates the signaling pathway of the UPR, in a similar fashion to that reported for mutants of PS1 linked to familial AD. It was clarified what molecules related to cell death are activated in the case of AD and we discovered that caspase-4 plays a key role in ER stress-induced apoptosis. Caspase-4 also seems to act upstream of the beta-amyloid-induced ER stress pathway, suggesting that activation of caspase-4 might mediate neuronal cell death in AD.
 ...
PMID:Induction of neuronal death by ER stress in Alzheimer's disease. 1536 92

The endoplasmic reticulum (ER) is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER. Excessive or long-termed stresses in the ER result in apoptotic cell death involving activation of caspase-12 and -3 and the Ask-1-JNK pathway. Eukaryotic cells can adapt for survival to deal with an accumulation of unfolded proteins in the ER by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP to facilitate protein folding. The induction system is termed the unfolded protein response (UPR). It has been reported that IRE1 and PERK, transmembrane kinases, and ATF6, a transmembrane transcription factor, are mediators of the UPR through sensing accumulation of unfolded proteins. Cell fates after ER stress are regulated by the balance of both apoptosis and the UPR signaling. In the nervous systems, astrocytes are well known to be resistant to ER stresses induced by ischemia and hypoxia. These findings raise the possibility that astrocytes possess a novel UPR signaling different from that of neuronal cells. Recently, we identified a novel ER stress sensor, OASIS, which is specifically expressed in astrocytes. This protein is a transmembrane protein containing the bZIP domain. The functional analyses of OASIS showed that 1) it was cleaved within the ER membrane in response to the ER stress, 2) overexpression of OASIS induced the transcription of GRP78/BiP mRNA through the activation of cyclic AMP responsive element (CRE) and ER stress responsive element (ERSE), and 3) its stable cell lines were resistant to ER stress compared with the control cells. These results indicate that the ER-resident transcription factor OASIS may be a candidate for leading astrocytes to protect against ER stress.
 ...
PMID:[The regulation of unfolded protein response by OASIS, a transmembrane bZIP transcription factor, in astrocytes]. 1557 42

Endoplasmic reticulum (ER) stress transducers IRE1, PERK and ATF6 are well known to transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins are accumulated in the ER. Here, we identified OASIS as a novel ER stress transducer. OASIS is a basic leucine zipper (bZIP) transcription factor of the CREB/ATF family with a transmembrane domain that allows it to associate with the ER. The molecule is cleaved at the membrane in response to ER stress, and its cleaved amino-terminal cytoplasmic domain, which contains the bZIP domain, translocates into the nucleus where it activates the transcription of target genes that are mediated by ER stress-responsive and cyclic AMP-responsive elements. Intriguingly, OASIS was induced at the transcriptional level during ER stress in astrocytes of the central nervous system, but not in other cell types examined. Furthermore, overexpression of OASIS resulted in induction of BiP and suppression of ER-stress-induced cell death, whereas knockdown partially reduced BiP levels and led to ER stress in susceptible astrocytes. Our results reveal pivotal roles for OASIS in modulating the unfolded protein response in astrocytes, and the possibility that cell type-specific UPR signalling also exists in other cells.
 ...
PMID:OASIS, a CREB/ATF-family member, modulates UPR signalling in astrocytes. 1566 55

Little is known about the molecular mechanisms underlying sleep. We show the induction of key regulatory proteins in a cellular protective pathway, the unfolded protein response (UPR), following 6 h of induced wakefulness. Using C57/B6 male mice maintained on a 12:12 light/dark cycle, we examined, in cerebral cortex, the effect of different durations of prolonged wakefulness (0, 3, 6, 9 and 12 h) from the beginning of the lights-on inactivity period, on the protein expression of BiP/GRP78, a chaperone and classical UPR marker. BiP/GRP78 expression is increased with increasing durations of sleep deprivation (6, 9 and 12 h). There is no change in BiP/GRP78 levels in handling control experiments carried out during the lights-off period. PERK, the transmembrane kinase responsible for attenuating protein synthesis, which is negatively regulated by binding to BiP/GRP78, is activated by dissociation from BiP/GRP78 and by autophosphorylation. There is phosphorylation of the elongation initiation factor 2alpha and alteration in ribosomal function. These changes are first observed after 6 h of induced wakefulness. Thus, prolonging wakefulness beyond a certain duration induces the UPR indicating a physiological limit to wakefulness.
 ...
PMID:Sleep deprivation induces the unfolded protein response in mouse cerebral cortex. 1571 65

The multiple implications of ER stress and the unfolded protein response in health and disease highlight the importance of identifying convenient monitoring systems for its onset under various experimental or physiological settings. A large volume of studies establish that induction of GRP78 is a marker for ER stress. GRP78, also referred to as BiP, is a central regulator for ER stress due to its role as a major ER chaperone with anti-apoptotic properties as well as its ability to control the activation of transmembrane ER stress sensors (IRE1, PERK, and ATF6) through a binding-release mechanism. In the following report, we present several methods to measure GRP78 induction. This can be achieved by measuring the Grp78 promoter activity or by measuring the level of Grp78 transcripts or GRP78 protein. These techniques can be applied to tissue culture cells as well as tissues and organs.
 ...
PMID:The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. 1580 10

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response. IRE1, PERK, ATF6, BiP, EDEM, lipid-linked oligosaccharides (LLOs), and XBP1 directly or indirectly participate in this process. This article provides methods used in our laboratory to quantitatively measure the accumulation of mRNAs encoding BiP and EDEM; splicing of XBP-1; cleavage of ATF6; inhibition of protein synthesis by PERK; and extension of LLOs under control and stress conditions.
 ...
PMID:Quantitative measurement of events in the mammalian unfolded protein response. 1580 12

Injury due to cold ischaemia-reperfusion (IR) represents a major cause of primary graft non-function following human liver transplantation. This major cellular response translates into a dramatic decrease in intracellular ATP concentration during the ischaemic phase, thus sensitizing cells to reperfusion shock. We postulated that IR-induced cellular damage might cause alterations of the secretory pathway, particularly at the level of endoplasmic reticulum (ER) function. Under these circumstances, the ER triggers an adaptive response named the 'unfolded protein response' (UPR). In this study, we show that the expression of BiP, CHOP/GADD153 and GADD34, known to be induced specifically upon ER stress, are differentially affected upon IR, thus suggesting that distinct ER stress responses are activated during each phase of transplantation. With an approach combining semi-quantitative RT-PCR and immunoblotting using phospho-specific antibodies, we show that the IRE-1 pathway is activated upon early ischaemia and, in a second phase, upon early reperfusion. This occurs through the atypical splicing of XBP-1 mRNA, its translation into a transcriptionally active XBP-1 protein and the subsequent increase in EDEM mRNA expression, and may also contribute to the observed reperfusion-induced activation of MAPK/SAPK. In contrast, we demonstrate that the PERK pathway, leading to inhibition of cap-dependent translation, is mainly activated upon reperfusion, as shown by PERK and eIF2alpha phosphorylation. PERK activation is detected restrictively in sinusoidal endothelial cells and could contribute to the exaggerated sensivity of this liver cell type to IR injury. These results correlate well with the observed defect in protein secretion and suggest that the biphasic ER stress response may influence liver secretory functions and, as a consequence, condition liver transplantation outcomes.
 ...
PMID:Distinct endoplasmic reticulum stress responses are triggered during human liver transplantation. 1591 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>