Genetic deletion of PKR abrogates TNF-induced activation of IκBα kinase, JNK, Akt and cell proliferation but potentiates p44/p42 MAPK and p38 MAPK activation

摘要: Double-stranded RNA-dependent protein kinase (PKR), a ubiquitously expressed serine/threonine kinase, has been implicated in the regulation or modulation of cell growth through multiple signaling pathways, but how PKR regulates tumor necrosis factor (TNF)-induced pathways is poorly understood. In present study, we used fibroblasts derived from gene-deleted mice to investigate role TNF-induced activation nuclear factor-κB (NF-κB), mitogen-activated kinases (MAPKs) and modulation. We found that wild-type mouse embryonic fibroblast (MEF), TNF induced NF-κB as measured by DNA binding deletion abolished this activation. This inhibition was associated with suppression inhibitory subunit (IκB)α (IKK) activation, IκBα phosphorylation degradation, p65 translocation, NF-κB-dependent reporter gene transcription. Akt needed for IKK also PKR. diminished PKR-deleted cells transfected receptor (TNFR) 1, TNFR-associated death domain TRAF2 plasmids; activated NF-κB-inducing p65, however, minimally affected. Among MAPKs, it interesting whereas c-Jun N-terminal (JNK) abolished, p44/p42 MAPK p38 potentiated cells. expression NF-κB-regulated products cyclin D1, c-Myc, matrix metalloproteinase-9, survivin, X-linked inhibitor-of-apoptosis (IAP), IAP1, Bcl-xL, A1/Bfl-1 Fas-associated protein-like IL-1β-converting enzyme-inhibitory MEF not PKR−/− Similarly, proliferation cells, completely suppressed Overall, our results indicate differentially signaling; IKK, JNK were positively regulated, negatively regulated.