Identification of a Novel Endoplasmic Reticulum Stress Response Element Regulated by XBP1

Misiewicz, Michael; Déry, Marc-André; Foveau, Bénédicte; Jodoin, Julie; Ruths, Derek; LeBlanc, Andréa C.

doi:10.1074/jbc.m113.457242

Cited by 45 publications

(37 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, studies have implicated Ire1␣ in modulation of ER stress-induced cell death. It has been shown that, in ER-stressed cells, XBP1 splicing and XBP1 protein expression decline with time (24,25,35). This decline correlates with cell death, and reconstitution of Ire1␣ activity improves cell survival (15,18).…”

Section: Discussionmentioning

confidence: 99%

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

Mujumdar

Banerjee

Chen

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

SM, Saluja AK. Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 306: G1011-G1020, 2014. First published April 3, 2014; doi:10.1152/ajpgi.00466.2013.-Pancreatic cancer is a devastating disease with a survival rate of Ͻ5%. Moreover, pancreatic cancer aggressiveness is closely related to high levels of prosurvival mediators, which can ultimately lead to rapid disease progression. One of the mechanisms that enables tumor cells to evade cellular stress and promote unhindered proliferation is the endoplasmic reticulum (ER) stress response. Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response (UPR). The UPR initially compensates for damage, but it eventually triggers cell death if ER dysfunction is severe or prolonged. Triptolide, a diterpene triepoxide, has been shown to be an effective compound against pancreatic cancer. Our results show that triptolide induces the UPR by activating the PKR-like ER kinase-eukaryotic initiation factor 2␣ axis and the inositol-requiring enzyme 1␣-X-box-binding protein 1 axis of the UPR and leads to chronic ER stress in pancreatic cancer. Our results further show that glucose-regulated protein 78 (GRP78), one of the major regulators of ER stress, is downregulated by triptolide, leading to cell death by apoptosis in MIA PaCa-2 cells and autophagy in S2-VP10 cells. endoplasmic reticulum stress; apoptosis; autophagy; pancreatic cancer; triptolide; glucose-regulated protein 78 PANCREATIC ADENOCARCINOMA is the fourth-leading cause of cancer-related death in the United States, with a 5-yr survival rate of Ͻ5% (17). Thus, understanding the pathobiology of pancreatic cancer is of utmost importance in developing innovative and effective therapies against it.Proper folding of secreted and transmembrane proteins occurs in the endoplasmic reticulum (ER). Many different physiological processes, highly secretory cells such as pancreatic ␤-cells, plasma B lymphocytes, and salivary glands, and pathological conditions such as hypoxia, ER Ca 2ϩ depletion, oxidative stress, viral infections, and cancer can cause an imbalance between ER protein folding load and capacity, leading to accumulation of unfolded proteins in the ER lumen, a condition known as "ER stress" (15, 31). Adaptation to ER stress is mediated by induction of the unfolded protein response (UPR), a signal transduction pathway that transmits information about protein folding status in the ER lumen to the nucleus to increase folding capacity, aiding in cell survival. The UPR involves three distinct components: 1) transcriptional induction of genes encoding ER-resident chaperones to facilitate protein folding, 2) translational attenuation to decrease the demands on the organelle, and 3) ER-associated degradation to degrade the accumulated unfolded proteins via the ubiquitin-proteasome pathway (18).In mammalian cells, the UPR is controlled by three transmembrane ER sensor...

show abstract

Section: Discussionmentioning

confidence: 99%

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

Mujumdar

Banerjee

Chen

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…According to the general concept [36,[41][42][43], appearance of abnormal protein leads to the dissociation of GRP78/BiP-IRE1, thereby IRE1 forms a dimer in the ER membrane, exhibits the RNase activity and splices the uncut XBP-1, which produces active XBP-1s. Its translation product XBP-1s has been reported to lure molecular chaperones under the control of the ER stress response element (ERSE) [44]. We suppose that such processes took place in the present cells.…”

Section: Grp78/bipmentioning

confidence: 97%

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

Kamada

Kusakabe

Sugimoto

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

View full text Add to dashboard Cite

“…Real-time quantitative reverse transcription (qRT)-PCR was used to measure gene transcript levels as previously described, 53 using commercially available pre-validated primers (Origene, Rockville, MD, USA) for NLRP1, IPAF-1, and AIM2. THP-1 monocyte mRNA was used as internal control for experiments.…”

Section: Methodsmentioning

confidence: 99%

Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation

et al. 2015

View full text Add to dashboard Cite

Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been welldefined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1 − / − and Casp1 − / − mice. NLRP1 immunopositive neurons were increased 25-to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-β-mediated neuroinflammation and Casp6-mediated axonal degeneration.

show abstract

Identification of a Novel Endoplasmic Reticulum Stress Response Element Regulated by XBP1

Cited by 45 publications

References 73 publications

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation

Contact Info

Product

Resources

About