The objective of this proposal is to further elucidate the role of the dsRNA-dependent protein kinase, PKR, in the cell. Evidence suggests that this kinase plays a crucial role in interferons response to viral infection and tumorigenesis and functions as a signal transducer in the regulation of dsRNA-activated pro-apoptotic genes such as Fas. Accordingly, the following aims will be pursued. 1. Using inducible cell-lines, we have shown that PKR is a key receptor- inducer for apoptosis mediated by dsRNA. The activation of PKR was concomitant with the induction of Fas and TNF alpha and required functional FADD to facilitate dsRNA-induced cell death. To extend our studies, we aim to further investigate the mechanisms of PKR induced apoptosis. This will include analyzing the mechanisms of Fas up- regulation by PKR and will incorporate examining the role of the known PKR substrate eIF2 as a possible effector molecules in PKR-mediated apoptosis. II. To complement our in vitro approach outlined above, we will examine whether cells from PKR knockouts as well as the animals themselves are defective in apoptotic signaling and/or host defense against malignant and viral induced disease. III. Finally, to complement both aims I and II, we have also generated viable transgenic lineages that over-express wild-type or trans-dominant- negative PKR variants. As in the above aims, embryonic fibroblasts and the animals themselves will be examined for their sensitivity or resistance to apoptosis, malignant transformation and viral disease.
| Elsby, Rachel; Heiber, Joshua F; Reid, Peter et al. (2011) The alpha subunit of eukaryotic initiation factor 2B (eIF2B) is required for eIF2-mediated translational suppression of vesicular stomatitis virus. J Virol 85:9716-25 |
| Pfeifer, Ingrid; Elsby, Rachel; Fernandez, Marilyn et al. (2008) NFAR-1 and -2 modulate translation and are required for efficient host defense. Proc Natl Acad Sci U S A 105:4173-8 |
| Goodman, Alan G; Smith, Jennifer A; Balachandran, Siddharth et al. (2007) The cellular protein P58IPK regulates influenza virus mRNA translation and replication through a PKR-mediated mechanism. J Virol 81:2221-30 |
| Greidinger, Eric L; Zang, YunJuan; Jaimes, Kimberly et al. (2006) A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum 54:661-9 |
| Balachandran, S; Roberts, P C; Brown, L E et al. (2000) Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13:129-41 |
