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lüll Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR) Pataer A; Vorburger SA; Barber GN; Chada S; Mhashilkar AM; Zou-Yang H; Stewart AL; Balachandran S; Roth JA; Hunt KK; Swisher SGCancer Res 2002[Apr]; 62 (8): 2239-43Adenoviral-mediated overexpression of the melanoma differentiation-associated gene 7 (Ad-mda7) induces apoptosis in a wide range of cancer cells, although themechanism is not well understood. We report that Ad-mda7 induces andactivates the double-stranded RNA-dependent protein kinase (PKR), which leads to phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2alpha) and the induction of apoptosis in lung cancer cells. Treatment with 2-aminopurine (2-AP), a serine/threonine kinase inhibitor, inhibits PKR activation, eIF2alpha phosphorylation, and apoptosis induction by Ad-mda7. Additionally, PKR null but not wild-type fibroblasts are resistant to Ad-mda7-induced apoptosis. These results suggest that the activation of PKR and its downstream targets may be a critical pathway for Ad-mda7-mediated apoptosis.|*Interleukins[MESH]|2-Aminopurine/pharmacology[MESH]|Adenoviridae/genetics[MESH]|Apoptosis/genetics/*physiology[MESH]|DNA-Binding Proteins/metabolism[MESH]|Enzyme Induction[MESH]|Enzyme Inhibitors/pharmacology[MESH]|Gene Transfer Techniques[MESH]|Genes, Tumor Suppressor[MESH]|Growth Substances/*genetics[MESH]|Humans[MESH]|Lung Neoplasms/enzymology/genetics/*pathology[MESH]|Phosphorylation[MESH]|Transcription Factors/metabolism[MESH]|Tumor Cells, Cultured[MESH]|Up-Regulation[MESH]|eIF-2 Kinase/antagonists & inhibitors/*biosynthesis/genetics[MESH] |