Abstract
An appreciation for the complex interactions between the NF-κB transcription factor and the Lin28 RNA binding protein/let-7 microRNA pathways has grown substantially over the past decade. Both the NF-κB and Lin28/let-7 pathways are master regulators impacting cell survival, growth and proliferation, and an understanding of how interfaces between these pathways participate in governing pluripotency, progenitor differentiation, and neuroplastic responses remains an emerging area of research. In this review, we provide a concise summary of the respective pathways and focus on the function of signaling interactions at both the transcriptional and post-transcriptional levels. Regulatory loops capable of providing both reinforcing and extinguishing feedback have been described. We highlight convergent findings in disparate biological systems and indicate future directions for investigation.
Highlights
While using mobility shift assays to study the gene rearrangement events that lead to antibody diversity, Ranjan Sen and David Baltimore discovered a nuclear factor that bound to the κ light-chain enhancer in extracts from B cell tumors and so called it nuclear factor kappa B (NF-κB) [1]
RelA, RelB, and c-Rel are synthesized as mature proteins and contain transcription activation domains (TADs) and the p50 and p52 subunits are the N-terminal cleavage products of the precursor proteins p105 and p100, respectively
The latent NF-κB dimer remains in the cytoplasm bound by inhibitory inhibitor of NF-κB (IκB) proteins
Summary
While using mobility shift assays to study the gene rearrangement events that lead to antibody diversity, Ranjan Sen and David Baltimore discovered a nuclear factor that bound to the κ light-chain enhancer in extracts from B cell tumors and so called it nuclear factor kappa B (NF-κB) [1]. Degradation of IκB exposes the NLS on NF-κB and allows for the dimer to stably translocate to the nucleus where it can bind cognate κB sites in the promoters and enhancers of target genes and regulate their transcription. The alternative ‘noncanonical’ pathway proceeds through IKKα-mediated phosphorylation of the NF-κB precursor protein, p100, at Ser176 and Ser180 leading to proteasomal removal of an IκB-resembling ankyrin repeat in p100 and the generation of p52 and its translocation to the nucleus with its main heterodimer partner, RelB. Critical features of the NF-κB pathway include the poised dimers latent in the cytoplasm which permit rapid response to stimuli, the canonical feedback mechanism in which NF-κB-mediated IκB induction allows regulated resolution of activation, and the numerous and diverse array of NF-κB activators and NF-κB-regulated genes We will focus on a more recently appreciated NF-κB target gene, the Lin RNA binding protein, and how interactions between the NF-κB and Lin pathways expand the repertoire of NF-κB to encompass largely reinforcing post-transcriptional gene regulatory mechanisms
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