Stimulation of phosphorylation of a nuclear protein (NP-34) in cultured Alzheimer's disease (AD) fibroblasts by interferon response element and other double-stranded oligonucleotides.

The interferon stimulated responsive elements (IRE), which correspond to nucleotide sequences between -103 and -85 (IRE18) and between -103 and -61 (IRE42), of the human 2',5'-oligoadenylate (2-5A) synthetase gene, were found to stimulate the phosphorylation of a number of proteins when added to nuclear extracts prepared from cultured AD fibroblasts; the most significant increase being a 34-kD protein, NP-34. Such an IRE-stimulated phosphorylation was less pronounced in normal fibroblast extracts. Other oligomers tested for IRE-like activity were found to be differentially effective. The relative activity of oligomers was correlated with their ability to be organized into an IRE42-like conformation. The IRE-dependent stimulation of the phosphorylation of nuclear proteins is most likely associated with the activation of a double-stranded DNA-dependent protein kinase (DNA-PK) since the IRE-stimulated phosphorylation of NP-34 was enhanced by the addition of purified HeLa DNA-PK, but reduced by a DNA-PK-specific monoclonal antibody.