Faculty Opinions recommendation of Caspase-mediated cleavage of IRE1 controls apoptotic cell commitment during endoplasmic reticulum stress.

Upon detecting endoplasmic reticulum (ER) stress, the unfolded protein response (UPR) orchestrates adaptive cellular changes to reestablish homeostasis. If stress resolution fails, the UPR commits the cell to apoptotic death. Here we show that in hematopoietic cells, including multiple myeloma (MM), lymphoma, and leukemia cell lines, ER stress leads to caspase-mediated cleavage of the key UPR sensor IRE1 within its cytoplasmic linker region, generating a stable IRE1 fragment comprising the ER-lumenal domain and transmembrane segment (LDTM). This cleavage uncouples the stress-sensing and signaling domains of IRE1, attenuating its activation upon ER perturbation. Surprisingly, LDTM exerts negative feedback over apoptotic signaling by inhibiting recruitment of the key proapoptotic protein BAX to mitochondria. Furthermore, ectopic LDTM expression enhances xenograft growth of MM tumors in mice. These results uncover an unexpected mechanism of cross-regulation between the apoptotic caspase machinery and the UPR, which has biologically significant consequences for cell survival under ER stress.

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p53-Independent Endoplasmic Reticulum Stress-Mediated Cytotoxicity of a Newcastle Disease Virus Strain in Tumor Cell Lines

Journal of Virology ◽

10.1128/jvi.02490-06 ◽

2007 ◽

Vol 81 (6) ◽

pp. 2817-2830 ◽

Cited By ~ 47

Author(s):

Zsolt Fábián ◽

Christine M. Csatary ◽

József Szeberényi ◽

Laszlo K. Csatary

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Endoplasmic Reticulum Stress ◽

Tumor Cell ◽

Newcastle Disease Virus ◽

Cell Lines ◽

Newcastle Disease ◽

Apoptotic Cell ◽

Transformed Cells ◽

Tumor Cell Lines

ABSTRACT While Newcastle disease virus (NDV) causes serious infections in birds, it is apparently nonpathogenic in mammalian species, including humans. Previous observations and small-scale clinical trials indicated that NDV exerts oncolytic effects. Isolates of NDV were found to have selective affinity to transformed cells. We previously showed that the attenuated NDV strain MTH-68/H causes apoptotic cell death in cultures of PC12 rat pheochromocytoma cells. The aim of the present study was to extend MTH-68/H cytotoxicity testing with human tumor cell lines and to analyze certain biochemical aspects of its oncolytic effect. MTH-68/H was found to be able to kill a wide range of transformed cells by apoptosis. While caspase-8 and caspase-9 are not involved in MTH-68/H-induced apoptosis, activation of caspase-3 and caspase-12 was detected in virus-infected PC12 cells. A human glioblastoma cell line with repressible expression of the p53 protein did not show any difference in MTH-68/H sensitivity in its p53-expressing and p53-depleted states, indicating that the apoptotic process induced by MTH-68/H does not depend on p53. Apoptosis was accompanied by virus replication in two tumor cell lines tested (PC12 cells and HeLa human cervical cells), and signs of endoplasmic reticulum stress (phosphorylation of protein kinase R-like endoplasmic reticulum kinase and eIF2α) were also detected in transformed cells. In contrast, proliferation of nontransformed mouse and rat fibroblast cell lines and human primary fibroblasts was not affected by MTH-68/H treatment. MTH-68/H thus selectively kills tumor cell cultures by inducing endoplasmic reticulum stress leading to p53-independent apoptotic cell death.

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Cystathionine Protects against Endoplasmic Reticulum Stress-induced Lipid Accumulation, Tissue Injury, and Apoptotic Cell Death

Journal of Biological Chemistry ◽

10.1074/jbc.m112.355172 ◽

2012 ◽

Vol 287 (38) ◽

pp. 31994-32005 ◽

Cited By ~ 35

Author(s):

Kenneth N. Maclean ◽

Lori S. Greiner ◽

Jeffrey R. Evans ◽

Sudesh K. Sood ◽

Sarka Lhotak ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Endoplasmic Reticulum Stress ◽

Lipid Accumulation ◽

Tissue Injury ◽

Apoptotic Cell ◽

Apoptotic Cell Death

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Protective Mechanism of KIOM-4 in Streptozotocin-Induced Pancreatic β-Cells Damage Is Involved in the Inhibition of Endoplasmic Reticulum Stress

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/231938 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Rui Zhang ◽

Jin Sook Kim ◽

Kyoung Ah Kang ◽

Mei Jing Piao ◽

Ki Cheon Kim ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Apoptotic Cell ◽

Cell Damage ◽

Initiation Factor ◽

Protective Mechanism ◽

Protective Effects ◽

Initiation Factor 2 ◽

Activating Transcription Factor

Endoplasmic reticulum stress-mediated apoptosis plays an important role in the destruction of pancreaticβ-cells and contributes to the development of type 1 diabetes. The present study examined the effect of KIOM-4, a mixture of four plant extracts, on streptozotocin- (STZ-) induced endoplasmic reticulum (ER) stress in rat pancreaticβ-cells (RINm5F). KIOM-4 was found to inhibit STZ-induced apoptotic cell death, confirmed by formation of apoptotic bodies and DNA fragmentation. STZ was found to induce the characteristics of ER stress; mitochondrial Ca2+overloading, enhanced ER staining, release of glucose-regulated protein 78 (GRP78), phosphorylation of RNA-dependent protein kinase (PKR) like ER kinase (PERK) and eukaryotic initiation factor-2α(eIF-2α), cleavage of activating transcription factor 6 (ATF6) and caspase 12, and upregulation of CCAAT/enhancer-binding protein-homologous protein (CHOP). However, KIOM-4 attenuated these changes induced by STZ. Furthermore, KIOM-4 suppressed apoptosis induced by STZ in CHOP downregulated cells using CHOP siRNA. These results suggest that KIOM-4 exhibits protective effects in STZ-induced pancreaticβ-cell damage, by interrupting the ER stress-mediated pathway.

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