Protein kinases play critical roles in the cellular regulatory circuits of higher organisms. The RNA-dependent protein kinase PKR, formerly called DAI, is well established as a key element of translational control mechanisms and of the interferon-induced antiviral response. More recently, its involvement in additional pathways has become apparent: these include apoptosis, differentiation, growth control, signal transduction, stress, and transformation. Cellular and viral components interact with PKR as activators, inhibitors, and substrates, emphasizing its pivotal position in cellular regulatory processes. The objectives of the research proposed here are to understand the regulation of PKR and the means by which it controls the activity of other cell proteins. PKR has recently been found to complex with and phosphorylate two important nuclear proteins. One is RNA helicase A (RHA), an essential DNA/RNA helicase which also serves as a transcription coactivator. The second is a nuclear factor of activated T cells (NFAT) known as NF90/NF45: this is a sequence-specific DNA binding protein which may be cell cycle-regulated. In particular, the project aims to elucidate the nature of the cellular macromolecules that activate PKR's protein kinase function, and the changes in the enzyme that are entailed in this activation. The novel protein-protein interactions involving PKR, RHA and NF90/NF45 will be defined and their implications for virus infection, gene expression, and cellular transformation will be explored. These proteins also interact with highly structured RNA molecules, including dsRNA and the adenovirus VA RNAs, suggestive of participation in RNA-regulated pathways. Understanding the activities, controls, and interactions of these cellular components may lead to strategies for intervention in cancer and viral disease.
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