Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B.Ashutosh Kumar, Jaharul Haque, Judith Lacoste et al.|Proceedings of the National Academy of Sciences|1994 The induction of interferon (IFN) genes by viruses or double-stranded RNA (dsRNA) requires the assembly of a complex set of transcription factors on responsive DNA elements of IFN gene promoters. One of the factors necessary for regulating IFN-beta gene transcription is nuclear factor NF-kappa B, the activation of which is triggered by dsRNA. It has previously been suggested that the dsRNA-activated p68 protein kinase (PKR) may act as an inducer-receptor, transducing the signal from dsRNA to NF-kappa B through phosphorylation of the inhibitor I kappa B. We present direct evidence that PKR can phosphorylate I kappa B-alpha (MAD-3) and activate NF-kappa B DNA binding activity in vitro. We further show that dsRNA induces an unusual phosphorylated form of I kappa B-alpha. The expression of a transdominant mutant PKR is able to perturb the dsRNA-mediated signaling pathway in vivo, suggesting a role for this kinase in IFN-beta gene induction.
H2AX phosphorylation driven by the SET-PP2A axis maintains glioma stem cell propertiesChunhua Han, Na Li, Ananya Banerjee et al.|Genes & Diseases|2025 Glioblastoma harbors a subpopulation of glioma stem cells (GSCs) that drive tumor relapse and invasion. Although GSC properties are known to be regulated by key transcription factors and chromatin remodeling, the mechanisms governing stemness-associated gene expression and the role of histone proteins in this process remain poorly understood. Here, we revealed that GSCs possessed an increased level of histone variant H2AX and phosphorylated H2AX at Ser 139 (γH2AX). CRISPR-Cas9-mediated deletion of H2AX demonstrated its critical role in maintaining GSC self-renewal, tumorigenicity, and the expression of multiple stemness-associated genes. Reintroduction of wild-type H2AX, but not the phosphorylation-deficient S139A mutant, restored GSC properties in H2AX-knockout cells, underscoring the importance of H2AX phosphorylation. We further identified that the elevated γH2AX levels in GSCs result from suppressed PP2A phosphatase activity, driven by increased expression of the SET oncoprotein. Pharmacological reactivation of PP2A effectively reduced γH2AX levels in GSCs. Collectively, our findings uncover a novel mechanism for GSC maintenance and highlight the SET-PP2A axis as a key regulator of γH2AX levels, offering a potential therapeutic target to disrupt GSC-driven tumor growth.