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Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death
- Source :
- Cell Death & Differentiation. 18:145-154
- Publication Year :
- 2010
- Publisher :
- Springer Science and Business Media LLC, 2010.
-
Abstract
- The eukaryotic cell responds to various forms of environmental stress by adjusting the rates of mRNA translation thus facilitating adaptation to the assaulting stress. One of the major pathways that control protein synthesis involves the phosphorylation of the α-subunit of eukaryotic initiation factor eIF2 at serine 51. Different forms of DNA damage were shown to induce eIF2α phosphorylation by using PERK, GCN2 or PKR. However, the specificity of the eIF2α kinases and the biological role of eIF2α phosphorylation pathway in the DNA damage response (DDR) induced by chemotherapeutics are not known. Herein, we show that PKR is the eIF2α kinase that responds to DDR induced by doxorubicin. We show that activation of PKR integrates two signaling pathways with opposing biological outcomes. More specifically, induction of eIF2α phosphorylation has a cytoprotective role, whereas activation of c-jun N-terminal kinase (JNK) by PKR promotes cell death in response to doxorubicin. We further show that the proapoptotic effects of JNK activation prevail over the cytoprotection mediated by eIF2α phosphorylation. These findings reveal that PKR can be an important inducer of cell death in response to chemotherapies through its ability to act independently of eIF2α phosphorylation.
- Subjects :
- DNA Repair
DNA repair
Eukaryotic Initiation Factor-2
Apoptosis
Protein Serine-Threonine Kinases
Biology
environment and public health
Cell Line
Mice
eIF-2 Kinase
Eukaryotic initiation factor
Animals
Humans
Phosphorylation
Molecular Biology
Original Paper
eIF2
EIF-2 kinase
Antibiotics, Antineoplastic
Kinase
Cell Biology
Protein kinase R
enzymes and coenzymes (carbohydrates)
Cytoprotection
Doxorubicin
Cancer research
biology.protein
Signal transduction
DNA Damage
Signal Transduction
Subjects
Details
- ISSN :
- 14765403 and 13509047
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Cell Death & Differentiation
- Accession number :
- edsair.doi.dedup.....97126c59c34797cdda87f44df1ed1209