The Anti-Apoptotic Role of the Unfolded Protein Response in Bcr-Abl Positive Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4527-4527
Author(s):  
Atsuko Tanimura ◽  
Toshiaki Yujiri ◽  
Yoshinori Tanaka ◽  
Yukio Tanizawa
Keyword(s):  
Unfolded Protein Response ◽  
Dominant Negative ◽  
Leukemic Cells ◽  
Luciferase Assay ◽  
Leukemia Cells ◽  
Unfolded Protein ◽  
Ph Chromosome ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Accumulation of unfolded or misfolded proteins within the endoplasmic reticulum triggers the unfolded protein response (UPR). Evidence from several studies suggests that the UPR is activated in various tumors and might play a crucial role in tumor growth. However, the role of the UPR in leukemia remains unclear. Therefore, to define the role of the UPR in leukemogenesis, we used p210 Bcr-Abl-expressing 32D myeloid cell lines (p210 32D). The mRNA expression of UPR-related genes, namely, a spliced form of X-box DNA-binding protein (XBP1) and glucose regulated protein 78 (GRP78), was increased in p210 32D. Luciferase assay indicated that p210 Bcr-Abl induced high levels of the transcriptional activity of the UPR element. Moreover, levels of the phosphorylated eIF2 alpha protein increased in p210 32D. Inhibition of the UPR using IRE1 and ATF6 dominant-negative mutants diminished the ability of Bcr-Abl to protect the cells from etoposide- and imatinib-induced apoptosis, but had no effect on the proliferation of p210 Bcr-Abl-transformed cells. We also evaluated the expression of UPR-related genes in primary leukemic cells from Ph chromosome-positive cells by real-time RT-PCR; it was found that these cells showed higher expression levels than the control cells. Taken together, these results for the first time suggested that UPR is a downstream target of the Bcr-Abl oncoprotein, and it plays the anti-apoptotic role of Bcr-Abl in Ph chromosome-positive leukemia cells.

The anti-apoptotic role of the unfolded protein response in Bcr-Abl-positive leukemia cells

2009 ◽  
Vol 33 (7) ◽  
pp. 924-928 ◽  
Author(s):  
Atsuko Tanimura ◽  
Toshiaki Yujiri ◽  
Yoshinori Tanaka ◽  
Masayuki Hatanaka ◽  
Noriyuki Mitani ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Leukemia Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

scholarly journals A Role for the DnaJ Homologue Scj1p in Protein Folding in the Yeast Endoplasmic Reticulum

1998 ◽  
Vol 143 (4) ◽  
pp. 921-933 ◽  
Author(s):  
Susana Silberstein ◽  
Gabriel Schlenstedt ◽  
Pam A. Silver ◽  
Reid Gilmore
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Physiological Role ◽  
Carboxypeptidase Y ◽  
Reporter Protein ◽  
Unfolded Protein ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Members of the eukaryotic heat shock protein 70 family (Hsp70s) are regulated by protein cofactors that contain domains homologous to bacterial DnaJ. Of the three DnaJ homologues in the yeast rough endoplasmic reticulum (RER; Scj1p, Sec63p, and Jem1p), Scj1p is most closely related to DnaJ, hence it is a probable cofactor for Kar2p, the major Hsp70 in the yeast RER. However, the physiological role of Scj1p has remained obscure due to the lack of an obvious defect in Kar2p-mediated pathways in scj1 null mutants. Here, we show that the Δscj1 mutant is hypersensitive to tunicamycin or mutations that reduce N-linked glycosylation of proteins. Although maturation of glycosylated carboxypeptidase Y occurs with wild-type kinetics in Δscj1 cells, the transport rate for an unglycosylated mutant carboxypeptidase Y (CPY) is markedly reduced. Loss of Scj1p induces the unfolded protein response pathway, and results in a cell wall defect when combined with an oligosaccharyltransferase mutation. The combined loss of both Scj1p and Jem1p exaggerates the sensitivity to hypoglycosylation stress, leads to further induction of the unfolded protein response pathway, and drastically delays maturation of an unglycosylated reporter protein in the RER. We propose that the major role for Scj1p is to cooperate with Kar2p to mediate maturation of proteins in the RER lumen.

scholarly journals IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2164
Author(s):  
Veronika J. M. Breitkopf ◽  
Gerhard Dobler ◽  
Peter Claus ◽  
Hassan Y. Naim ◽  
Imke Steffen
Keyword(s):  
Unfolded Protein Response ◽  
Intestinal Cell ◽  
Intestinal Cells ◽  
Tissue Tropism ◽  
Cell Type ◽  
Unfolded Protein ◽  
Tbev Strain ◽  
The Unfolded Protein Response ◽  
Protein Response

Tick-borne flaviviruses (TBFV) can cause severe neurological complications in humans, but differences in tissue tropism and pathogenicity have been described for individual virus strains. Viral protein synthesis leads to the induction of the unfolded protein response (UPR) within infected cells. The IRE1 pathway has been hypothesized to support flavivirus replication by increasing protein and lipid biogenesis. Here, we investigated the role of the UPR in TBFV infection in human astrocytes, neuronal and intestinal cell lines that had been infected with tick-borne encephalitis virus (TBEV) strains Neudoerfl and MucAr-HB-171/11 as well as Langat virus (LGTV). Both TBEV strains replicated better than LGTV in central nervous system (CNS) cells. TBEV strain MucAr-HB-171/11, which is associated with gastrointestinal symptoms, replicated best in intestinal cells. All three viruses activated the inositol-requiring enzyme 1 (IRE1) pathway via the X-box binding protein 1 (XBP1). Interestingly, the neurotropic TBEV strain Neudoerfl induced a strong upregulation of XBP1 in all cell types, but with faster kinetics in CNS cells. In contrast, TBEV strain MucAr-HB-171/11 failed to activate the IRE1 pathway in astrocytes. The low pathogenic LGTV led to a mild induction of IRE1 signaling in astrocytes and intestinal cells. When cells were treated with IRE1 inhibitors prior to infection, TBFV replication in astrocytes was significantly reduced. This confirms a supporting role of the IRE1 pathway for TBFV infection in relevant viral target cells and suggests a correlation between viral tissue tropism and the cell-type dependent induction of the unfolded protein response.

scholarly journals Degradation of a Short-lived Glycoprotein from the Lumen of the Endoplasmic Reticulum: The Role of N-linked Glycans and the Unfolded Protein Response

1999 ◽  
Vol 10 (12) ◽  
pp. 4059-4073 ◽  
Author(s):  
Maddalena de Virgilio ◽  
Claudia Kitzmüller ◽  
Eva Schwaiger ◽  
Michael Klein ◽  
Gert Kreibich ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
The Other ◽  
Slow Phase ◽  
Type I ◽  
Unfolded Protein ◽  
Other Hand ◽  
The Unfolded Protein Response ◽  
Protein Response

We are studying endoplasmic reticulum–associated degradation (ERAD) with the use of a truncated variant of the type I ER transmembrane glycoprotein ribophorin I (RI). The mutant protein, RI332, containing only the N-terminal 332 amino acids of the luminal domain of RI, has been shown to interact with calnexin and to be a substrate for the ubiquitin-proteasome pathway. When RI332 was expressed in HeLa cells, it was degraded with biphasic kinetics; an initial, slow phase of ∼45 min was followed by a second phase of threefold accelerated degradation. On the other hand, the kinetics of degradation of a form of RI332 in which the single used N-glycosylation consensus site had been removed (RI332-Thr) was monophasic and rapid, implying a role of the N-linked glycan in the first proteolytic phase. RI332degradation was enhanced when the binding of glycoproteins to calnexin was prevented. Moreover, the truncated glycoprotein interacted with calnexin preferentially during the first proteolytic phase, which strongly suggests that binding of RI332 to the lectin-like protein may result in the slow, initial phase of degradation. Additionally, mannose trimming appears to be required for efficient proteolysis of RI332. After treatment of cells with the inhibitor of N-glycosylation, tunicamycin, destruction of the truncated RI variants was severely inhibited; likewise, in cells preincubated with the calcium ionophore A23187, both RI332 and RI332-Thr were stabilized, despite the presence or absence of the N-linked glycan. On the other hand, both drugs are known to trigger the unfolded protein response (UPR), resulting in the induction of BiP and other ER-resident proteins. Indeed, only in drug-treated cells could an interaction between BiP and RI332 and RI332-Thr be detected. Induction of BiP was also evident after overexpression of murine Ire1, an ER transmembrane kinase known to play a central role in the UPR pathway; at the same time, stabilization of RI332 was observed. Together, these results suggest that binding of the substrate proteins to UPR-induced chaperones affects their half lives.

scholarly journals Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in AML

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5931-5940 ◽  
Author(s):  
Simon Haefliger ◽  
Christiane Klebig ◽  
Kerstin Schaubitzer ◽  
Julian Schardt ◽  
Nikolai Timchenko ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Disulfide Isomerase ◽  
Leukemic Cells ◽  
Stem Loop ◽  
Unfolded Protein ◽  
Loop Region ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Protein Disulfide

Abstract Deregulation of the myeloid key transcription factor CEBPA is a common event in acute myeloid leukemia (AML). We previously reported that the chaperone calreticulin is activated in subgroups of AML patients and that calreticulin binds to the stem loop region of the CEBPA mRNA, thereby blocking CEBPA translation. In this study, we screened for additional CEBPA mRNA binding proteins and we identified protein disulfide isomerase (PDI), an endoplasmic reticulum (ER) resident protein, to bind to the CEBPA mRNA stem loop region. We found that forced PDI expression in myeloid leukemic cells in fact blocked CEBPA translation, but not transcription, whereas abolishing PDI function restored CEBPA protein. In addition, PDI protein displayed direct physical interaction with calreticulin. Induction of ER stress in leukemic HL60 and U937 cells activated PDI expression, thereby decreasing CEBPA protein levels. Finally, leukemic cells from 25.4% of all AML patients displayed activation of the unfolded protein response as a marker for ER stress, and these patients also expressed significantly higher PDI levels. Our results indicate a novel role of PDI as a member of the ER stress–associated complex mediating blocked CEBPA translation and thereby suppressing myeloid differentiation in AML patients with activated unfolded protein response (UPR).

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