The Nuclear Factor-κB Signaling Network: Insights from Systems Approaches

Abstract

This chapter reviews the nature of bipartite nuclear factor-κB (NF-κB) regulatory pathways activated in response to monokines produced as a consequence of viral infection, and those involved in mediating RNA viral infection. The chapter discusses work using mRNA profiling studies to determine the genetic networks downstream of NF-κB in response to monokines and RNA virus replication. Inhibition of reactive oxygen species (ROS) formation blocks Ser-276 phosphorylation and NF-κB-dependent gene expression without affecting NF-κB translocation. It was also found that RelA Ser-276 phosphorylation allows complex formation with the cyclin-dependent kinases (CDK)-9/Ccn T1, known as positive transcription elongation factor-b (PTEF-b). Reovirus is a segmented double-stranded RNA (dsRNA) virus that induces cellular apoptosis in an NF-κB-dependent manner. In a study, the tTA-IκB-α Mut cell system was exposed to reovirus for various times from 0 to 10 h in the presence or absence of functional NF-κB signaling. The major pathways are now understood to be composed of bipartite signaling modules whose actions affect nuclear translocation and, separately, transcription factor activation. The chapter also reviews systematic approaches to understanding the signaling pathway, including proteomics, mathematical modeling, real-time imaging, and gene network analyses.