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Involvement of proteolytic activation of protein kinase R in the apoptosis of PC12 pheochromocytoma cells.
- Source :
-
Cellular and molecular neurobiology [Cell Mol Neurobiol] 2008 May; Vol. 28 (3), pp. 443-56. Date of Electronic Publication: 2007 Dec 14. - Publication Year :
- 2008
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Abstract
- Protein kinase R (PKR) is a serine/threonine-specific protein kinase implicated in the control of cell growth, differentiation, interferon-induced antiviral response, and induction of apoptosis. It is activated by various stress signals and growth factors. Activated PKR phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha), thereby inhibiting the initiation of translation. PKR also mediates the activation of several transcription factors (STAT1, p53, and NFkappaB) regulating both pro- and antiapoptotic mechanisms. In the present work, we studied the signaling pathways leading to PKR activation and apoptosis in PC12 rat pheochromocytoma cells, a model system of neuronal differentiation and cell death. We found that administration of various apoptosis inducing agents and conditions (serum starvation, anisomycin, LY294002, etoposide, and cisplatin) led to the proteolytic cleavage of PKR in PC12 cells. This cleavage was in strong correlation with the time kinetics of DNA fragmentation and morphological alterations characteristic of apoptosis. PKR was activated by the proteolytic cleavage: increased phosphorylation of eIF2alpha was found to run parallel with PKR cleavage. The activation of caspase-3 and caspase-9 was stimulated by all apoptosis inducing agents used in this study. The activation of caspase-3 preceded the cleavage of PKR after serum withdrawal, anisomycin and etoposide treatment, while coincided with it in cells treated with LY294002 or cisplatin. These observations suggest that early activation of caspase-3 is upstream of PKR proteolysis and that proteolytic activation of PKR may play a general role in the apoptosis of PC12 cells induced by various forms of cellular stress.
- Subjects :
- Adrenal Gland Neoplasms enzymology
Adrenal Gland Neoplasms metabolism
Animals
Anisomycin pharmacology
Caspase 3 metabolism
Caspase 9 metabolism
Chromones pharmacology
Culture Media, Serum-Free pharmacology
DNA Fragmentation
Enzyme Activation
Enzyme Inhibitors pharmacology
Morpholines pharmacology
PC12 Cells
Peptide Hydrolases metabolism
Pheochromocytoma enzymology
Pheochromocytoma metabolism
Protein Processing, Post-Translational physiology
Protein Synthesis Inhibitors pharmacology
Rats
Adrenal Gland Neoplasms pathology
Apoptosis
Pheochromocytoma pathology
eIF-2 Kinase metabolism
eIF-2 Kinase physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0272-4340
- Volume :
- 28
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cellular and molecular neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 18080832
- Full Text :
- https://doi.org/10.1007/s10571-007-9245-y