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)

Induction of drug-metabolizing microsomal cytochromes p450 (p450s) results in a striking proliferation of the smooth endoplasmic reticulum (ER). Overexpression of P450s in yeast and cultured cells produces a similar response. The signals mediating this process are not known but probably involve signal transduction pathways involved in the unfolded protein response (UPR) or the ER overload response (EOR). We have examined the temporal response of specific genes in these pathways and genes globally to overexpression of p450 in cultured cells. Activity of NFkappaB, an EOR component, was substantially increased by overexpression of full-length p450 2C2 or a chimera with the 28-amino acid signal anchor sequence of p450 2C2 in HepG2 cells, and the activation correlated temporally with the accumulation of p450 in the cells. In the UPR pathway, activation of the transcription factor XBP1 by IRE1 also correlated with the accumulation of p450 in the cells, and in contrast, maximum activation of the BiP/grp78 promoter preceded the accumulation. Differential effects of expression of p450 on apoptosis were observed in nonhepatic COS1 and hepatic HepG2 cells. In COS1 cells, apoptosis was induced, and this correlated with sustained activation of the pro-apoptotic JNK pathway, induction of CHOP, and an absence of the increased NFkappaB activity. In HepG2 cells, JNK was only transiently activated, and CHOP expression was not induced. As assessed by DNA microarray analysis, up-regulation of signaling genes was predominant including those involved in anti-apoptosis and ER stress. These results suggest that both the EOR and UPR pathways are involved in the cellular response to induction of p450 expression and that in hepatic cells genes are also induced to block apoptosis, which may be a physiologically relevant response to prevent cell death during xenobiotic induced expression of p450 in the liver.
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PMID:Gene expression changes associated with the endoplasmic reticulum stress response induced by microsomal cytochrome p450 overproduction. 1471 36

Accumulation of misfolded proteins within the lumen of the mammalian endoplasmic reticulum (ER) activates the unfolded protein response (UPR). ATF6 and Ire1p are ER-associated proteins that control UPR-specific transcription systems in mammals; UPR signaling involves cleavage of ATF6 and splicing of XBP1 mRNA initiated by Ire1p. We tested the hypothesis that activation of ATF6 and/or Ire1p determines the levels of mRNAs derived from target genes encoding GRP78/BiP and EDEM. By subjecting dermal fibroblasts to multiple stresses, strong correlations were found between ATF6 activation and XBP1 splicing, and between GRP78/BiP mRNA and EDEM mRNA accumulation. Surprisingly, there was no reasonable correlation between activation of either signal transducer with accumulation of either target transcript. Thus, ATF6 and Ire1p signaling do not define the magnitude of UPR-dependent mRNA increases, even though they may be necessary for gene activation, suggesting the existence of additional stress-sensitive factors acting as "coincidence detectors" for transcript accumulation.
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PMID:Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts. 1506 70

Anticancer drugs often show complex mechanisms of action, including effects on multiple cellular targets. Detailed understanding of these intricate effects is important for the understanding of cytotoxicity. In this study, we examined apoptosis induction by ellipticines, a class of cytotoxic plant alkaloids known to inhibit topoisomerase II. The potent ellipticine derivative 6-propanamine ellipticine (6-PA-ELL) induced rapid apoptosis in MDA-MB-231 breast cancer cells, preceded by a conformational change in Bak and cytochrome c release. Experiments using knock-out mouse embryo fibroblasts established that Bak was of particular importance for cytotoxicity. 6-PA-ELL increased the expression of the endoplasmic reticulum chaperones GRP78/BiP and GRP94, suggesting induction of endoplasmic reticulum stress. Induction of GRP78 expression was dependent on the endoplasmic reticulum stress response element (ERSE) of the GRP78 promoter. Examination of different ellipticine derivatives revealed a correlation between pro-apoptotic activity and the ability to induce GRP78 expression. Furthermore, 6-PA-ELL was found to induce splicing of the mRNA encoding the XBP1 transcription factor, characteristic of endoplasmic reticulum stress, and to induce activation of the endoplasmic reticulum-specific caspase-12 in mouse colon cancer cells. We finally demonstrate that 6-PA-ELL induces apoptotic signaling also in enucleated cells, consistent with the existence of a cytoplasmic target for this compound. Our data suggest that induction of endoplasmic reticulum stress may contribute to the cytotoxicity of ellipticines.
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PMID:Induction of endoplasmic reticulum stress by ellipticine plant alkaloids. 1507 93

ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. The Herp gene, one of the most highly inducible genes under ER stress, encodes an ER membrane protein containing a ubiquitin-like domain with unknown functions, and carries ERSE-II in addition to ERSE in its promoter. In this report, we show that ERSE-II allows the NF-Y-dependent binding of ATF6 as in the case of ERSE and NF-Y-independent binding of XBP1 as in the case of UPRE, and that transcription from ERSE-II is mitigated in the absence of XBP1. Accordingly, the induction of Herp mRNA was diminished in the absence of XBP1 whereas that of BiP mRNA was not affected. These results may help in understanding the role of Herp in the quality control system in the ER.
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PMID:Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. 1559 91

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.
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PMID:Quantitative measurement of events in the mammalian unfolded protein response. 1580 12

The unfolded protein response (UPR) events triggered by the accumulation of unfolded protein in endoplasmic reticulum (ER) activate the three UPR signaling pathways mediated by IRE1, ATF6 and PERK. Spliced XBP1 mRNA induced by activated IRE1 is translated to the protein, a potent transcription factor that induces BiP expression. XBP1 is also induced by activated ATF6. It is thus thought to be an important marker reflecting both IRE1 and ATF6 signaling in response to ER stress. For quantitative measurement of XBP1 gene expression, it is important to distinguish between the spliced and non-spliced form of XBP1 mRNA. We have developed a new method to detect the spliced XBP1 mRNA by means of real-time PCR and we compared the result with measurements of the expression of the ER stress inducible gene BiP. A good correlation was found between spliced XBP1 expression and BiP expression. Thus, our method may be useful for simple and quantitative evaluation of ER stress.
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PMID:Quantitative measurement of spliced XBP1 mRNA as an indicator of endoplasmic reticulum stress. 1677 4

The unfolded protein response (UPR) is a cellular recovery mechanism activated by endoplasmic reticulum (ER) stress. The UPR is coordinated with the ER-associated degradation (ERAD) to regulate the protein load at the ER. In the present study, we tested how membrane protein biogenesis is regulated through the UPR in epithelia, using the cystic fibrosis transmembrane conductance regulator (CFTR) as a model. Pharmacological methods such as proteasome inhibition and treatment with brefeldin A and tunicamycin were used to induce ER stress and activate the UPR as monitored by increased levels of spliced XBP1 and BiP mRNA. The results indicate that activation of the UPR is followed by a significant decrease in genomic CFTR mRNA levels without significant changes in the mRNA levels of another membrane protein, the transferrin receptor. We also tested whether overexpression of a wild-type CFTR transgene in epithelia expressing endogenous wild-type CFTR activated the UPR. Although CFTR maturation is inefficient in this setting, the UPR was not activated. However, pharmacological induction of ER stress in these cells also led to decreased endogenous CFTR mRNA levels without affecting recombinant CFTR message levels. These results demonstrate that under ER stress conditions, endogenous CFTR biogenesis is regulated by the UPR through alterations in mRNA levels and posttranslationally by ERAD, whereas recombinant CFTR expression is regulated only by ERAD.
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PMID:Endoplasmic reticulum stress and the unfolded protein response regulate genomic cystic fibrosis transmembrane conductance regulator expression. 1700 2

The endoplasmic reticulum (ER) is an organelle in which secretory and transmembrane proteins are folded or processed, and is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER lumen. Recently, ER stress has been reported to be linked to neuronal death in various neurodegenerative diseases. Neurons contain the ER not only in the soma, but also in the dendrites, thus presenting a different case to non-neuronal cells. The ER in the dendrites has potential functions in local protein synthesis and sorting of synthesized proteins to postsynaptic membranes. It raises the possibility that ER stress could occur locally in the dendrites. Here we showed that ER stress sensors, inositol-requiring 1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) exist in the ER of both soma and dendrites in primary mouse neurons, and that under ER stress conditions, GRP78/BiP and phosphorylated eIF2alpha are induced. Furthermore, XBP1 mRNA was localized in the proximal dendrites where IRE1 was rapidly phosphorylated in response to ER stress. These results indicate that the ER in dendrites could respond to ER stress and retain the capacity of protein quality control.
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PMID:Endoplasmic reticulum stress response in dendrites of cultured primary neurons. 1736 44

Homoharringtonine has been shown to lead to apoptosis of leukemic cells in several studies. Here we showed that the endoplasmic reticulum (ER) may be the initial site of apoptotic signal induced by homoharringtonine in MUTZ-1 cells. After incubation with homoharringtonine, the percentage of apoptotic MUTZ-1 cells increased in a time-dependent manner, Ca(2+) translocated from ER pool to cytosol, the mitochondrial membrane potential decreased, and Bid protein translocated from ER to mitochondria. The activation of ER stress-associated proapoptotic factor CHOP and ER chaperones BiP and XBP1 genes followed by cleavage of caspase-3 but not caspase-4 protein were also observed.
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PMID:Homoharringtonine-induced apoptosis of MDS cell line MUTZ-1 cells is mediated by the endoplasmic reticulum stress pathway. 2709 92

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.
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PMID:Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. 1752 89


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