Back to Search
Start Over
Inhibition of PKR protects against tunicamycin-induced apoptosis in neuroblastoma cells.
- Source :
-
Gene [Gene] 2014 Feb 15; Vol. 536 (1), pp. 90-6. Date of Electronic Publication: 2013 Dec 14. - Publication Year :
- 2014
-
Abstract
- Endoplasmic reticulum (ER) dysfunction is thought to play a significant role in several neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, cerebral ischemia, and the prion diseases. ER dysfunction can be mimicked by cellular stress signals such as disruption of calcium homeostasis, inhibition of protein glycosylation, and reduction of disulfide bonds, which results in accumulation of misfolded proteins in the ER and leads to cell death by apoptosis. Tunicamycin, which is an inhibitor of protein glycosylation, induces ER stress and apoptosis. In this study, we examined the involvement of double stranded (ds) RNA-activated protein kinase PKR in tunicamycin-induced apoptosis. We used overexpression of the trans-dominant negative, catalytically inactive mutant K296R to inhibit PKR activity in neuroblastoma cells. We demonstrate that inhibition of PKR activation in response to tunicamycin protects neuronal cells from undergoing apoptosis. Furthermore, K296R overexpressing cells show defective PKR activation, delayed eIF2α phosphorylation, dramatically delayed ATF4 expression. In addition, both caspase-3 activation and C/EBP homologous protein (CHOP, also known as GADD153) induction, which are markers of apoptotic cells, are absent from K296R overexpression cells in response to tunicamycin. These results establish that PKR activation plays a major regulatory role in induction of apoptosis in response to ER stress and indicates the potential of PKR as possible target for neuroprotective therapeutics.<br /> (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Subjects :
- Amino Acid Substitution
Arginine genetics
Cytoprotection genetics
Endoplasmic Reticulum genetics
Endoplasmic Reticulum metabolism
Enzyme Activation drug effects
Enzyme Activation genetics
Humans
Lysine genetics
Mutation, Missense physiology
Neuroblastoma genetics
Neuroblastoma metabolism
Tumor Cells, Cultured
eIF-2 Kinase genetics
eIF-2 Kinase immunology
eIF-2 Kinase metabolism
Antibodies, Monoclonal pharmacology
Apoptosis drug effects
Cytoprotection drug effects
Neuroblastoma pathology
Tunicamycin pharmacology
eIF-2 Kinase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0038
- Volume :
- 536
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gene
- Publication Type :
- Academic Journal
- Accession number :
- 24334130
- Full Text :
- https://doi.org/10.1016/j.gene.2013.11.074