Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling - PubMed (original) (raw)

Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling

S Balachandran et al. EMBO J. 1998.

Abstract

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, PKRdelta6. Following induction, the growth of the wild-type PKR-expressing cells was similar to that of cells transfected with vector alone, while cells expressing PKRdelta6 became malignantly transformed. Significantly, treatment with dsRNA caused the wild-type PKR-overexpressing cells to undergo programed cell death while, conversely, cells expressing PKRdelta6 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 PKRdelta6. 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.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Virology. 1995 Nov 10;213(2):413-24 - PubMed
    1. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11894-8 - PubMed
    1. EMBO J. 1995 Dec 15;14(24):6095-106 - PubMed
    1. Cell. 1996 Jun 14;85(6):817-27 - PubMed
    1. Cell. 1996 Jul 12;86(1):147-57 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources