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| The EMBO Journal
(1998) 17, 6888–6902, doi:10.1093/emboj/17.23.6888 |
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| Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling |
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| Siddharth Balachandran1, Caryn N. Kim2, Wen-Chen Yeh3, Tak W. Mak3, Kapil Bhalla2 and Glen N. Barber1 |
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1 Department of Microbiology and Immunology and Winship Cancer Center, Atlanta, GA 30322, USA 2 Department of Medicine and Winship Cancer Center, Emory University School of Medicine, Atlanta, GA 30322, USA 3 Amgen Institute, University of Toronto and Ontario Cancer Institute, 610 University Avenue, Toronto, M2G 2C1, Canada To whom correspondence should be addressed Glen N. Barber, gbarber@emory.edu Received 24 June 1998; Revised 5 October 1998; Accepted 5 October 1998. |
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| Abstract |
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The dsRNA-dependent protein kinase (PKR) is considered to play a key role in interferon-mediated host defense against viral infection and conceivably malignant transformation. To investigate further the mechanisms of PKR-induced growth inhibition, we have developed tetracycline-inducible murine cell lines that express wild-type PKR or a catalytically inactive PKR variant, PKR 6. Following induction, the growth of the wild-type PKR-expressing cells was similar to that of cells transfected with vector alone, while cells expressing PKR6 became malignantly transformed. Significantly, treatment with dsRNA caused the wild-type PKR-overexpressing cells to undergo programed cell death while, conversely, cells expressing PKR6 were completely resistant. Our studies demonstrated that activation of PKR induces the expression of members of the tumor necrosis factor receptor (TNFR) family, including Fas (CD95/Apo-1) and pro-apopotic Bax. In contrast, transcripts representing Fas, TNFR-1, FADD (Fas-associated death domain), FLICE, Bad and Bax were ablated in cells expressing PKR6. The involvement of the death receptors in PKR-induced apoptosis was underscored by demonstrating that murine fibroblasts lacking FADD were almost completely resistant to dsRNA-mediated cell death. Thus, PKR, a key cellular target for viral repression, is a receptor/inducer for the induction of pro-apoptotic genes by dsRNA and probably functions in interferon-mediated host defense to trigger cell death in response to virus infection and perhaps tumorigenesis. |
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| Keywords: apoptosis, dsRNA-dependent protein kinase, FADD, tumorigenesis, viral infection |
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