Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis.
The transcription factor E2F-1 induces cell cycle progression at the G1/S checkpoint, and deregulation of E2F-1 provokes apoptosis in a wide variety of malignant cells. To date only p14(ARF) and p73, a p53 homologue, have been identified as E2F-1-inducible genes capable of mediating an apoptotic response. Here we show that adenovirus-mediated E2F-1 overexpression in cancer cells induces expression and autophosphorylation of the double-stranded RNA-dependent protein kinase PKR leading to phosphorylation of its downstream target, the alpha-subunit of the eukaryotic translation initiation factor 2 (eIF-2alpha) and to apoptotic cell death. This PKR-dependent apoptosis occurs in cell lines with mutated p53 and in cell lines with mutated p53 and p73, and is significantly reduced by the chemical inhibition of PKR activation. Further, PKR(-/-) mouse embryo fibroblasts, but not PKR(+/+) mouse embryo fibroblasts, demonstrate significant resistance to E2F-1-induced apoptosis. We conclude that an important pathway of E2F-1-mediated apoptosis is dependent on PKR activation and does not require p53 or p73.
Vorburger
Stephan A
SA
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Pataer
Abujiang
A
Yoshida
Kazumi
K
Barber
Glen N
GN
Xia
Weiya
W
Chiao
Paul
P
Ellis
Lee M
LM
Hung
Mien-Chie
MC
Swisher
Stephen G
SG
Hunt
Kelly K
KK
D017209:Apoptosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D009687:Nuclear Proteins; D010766:Phosphorylation; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D019892:eIF-2 Kinase