The Emerging Role of the Interferon-Induced PKR Protein Kinase as an Apoptotic Effector: A New Face of Death?

Abstract

Recent research has thrown a spotlight on the interferon (IFN)-induced PKR protein kinase, implicating it as an important effector of apoptosis induced by several cellular stress conditions, including viral infection, cytokine treatment, and growth factor deprivation. In this review, we summarize the evidence for the role of PKR as a death accomplice and discuss how PKR might promote cell demise in light of current knowledge of the molecular mechanisms of apoptosis. Given its new found role and its established antiviral function, it is no wonder that PKR is a popular target for viral evasion of the host defense. PKR-dependent apoptosis may offer a novel cell-death pathway for specific manipulation in therapeutic strategies against apoptosis-related diseases.

High Amino Acid Variability Within the Ns5a of Hepatitis C Virus (Hcv) Is Associated With Hepatocellular Carcinoma in Patients With Hcv–1B-Related Cirrhosis

“…67,70 Regulation of PKR probably implicates various cellular pathways that may be different depending on the cell type and stimulatory events. 71 In fact, HCV-NS5A seems to act over different cellular factors for the regulation of cellular metabolism, promoting cell growth and perturbing mitogenic signaling pathways. [72][73][74] In addition, HCV proteins also inhibit the JAK-STAT pathway that may be important in cellular proliferation.…”

PKR; a sentinel kinase for cellular stress

“…PKR and growth factor signaling PKR has growth regulatory properties and acts as an oncogene when catalytically inactive mutants are overexpressed in NIH3T3 cells (reviewed in Clemens and Elia, 1997;Tan and Katze, 1999). Transformation could be driven in part by a deregulation of protein synthesis initiation since mutant forms of eIF2a, a PKR substrate, are also transforming oncogenes in this assay (Donze et al, 1995).…”

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

“…89 Activated PKR inhibits protein synthesis by phosphorylating eIF2␣, a molecule required for protein translation initiation events. [113][114][115] Until recently, PKR was known only as a component of the host anti-viral defense mechanism where double-stranded viral RNA activated the protein. [113][114][115] To account for non-viral activation of PKR in response to stress, a cellular PKR regulator, RAX, was identified.…”

“…[113][114][115] Until recently, PKR was known only as a component of the host anti-viral defense mechanism where double-stranded viral RNA activated the protein. [113][114][115] To account for non-viral activation of PKR in response to stress, a cellular PKR regulator, RAX, was identified. 112 RAX is activated after stress-induced phosphorylation by an as yet unidentified SAPK.…”