Year: 2006
Type: article
Abstract: NF-κB was discovered over 20 years ago, and while the knowledge of this transcription factor has been considerably expanded, it is still not completely understood how a single signaling pathway regulates such a diverse array of events in cells.One of the ways in which this transcription factor may target a variety of genes under different conditions is through post-translational modifications that regulate how the complex binds to gene promoters, as well as how it binds to other co-factors.This thesis is designed to investigate how these modifications, specifically phosphorylation, regulate gene expression and control NF-κB mediated events.Chapter one is a general introduction to NF-κB, highlighting the members of this family, the activation pathway, and the various modifications known to occur to members of the complex.This chapter also discusses some of the known NF-κB target genes as well as diseases that are known to occur, at least in part due to deregulated NF-κB activity.Chapter two investigates the effect of phosphorylation on the stability of IκBβ, an inhibitor of NF-κB.We have found that IκBβ is normally unstable in the absence of p65 protein, however a hyperphosphorylated form of IκBβ is resistant to proteasome mediated degradation, and is stable under these conditions.We further show that this regulation is important for maintenance of normal cell growth in mouse embryo fibroblasts.Chapters three and four iii focus on a different aspect of phosphorylation.In contrast to how protein phosphorylation controls stability, these chapters are designed specifically to determine how this modification affects target gene transcription.The goal of this part of the thesis is to further elucidate whether specific phosphorylation at particular resides can differentially affect sub-sets of endogenous genes.Finally, chapter five discusses the attempts to determine the role of NF-κB post-translation modification in other cell types, as well as discuss the importance of increasing our current knowledge as to how this complicated transcription factor signals.Insight into how NF-κB differentially regulates subsets of genes may allow for development of specific therapeutic targets.Currently, drugs that inhibit NF-κB on a broad level are in use, however these types of treatments may have undesirable side effects due to non-specific inhibition of other beneficial pathways in the cell.The ability to develop more specific inhibitors that affect only a small number of genes important in a particular disease will allow for more efficient therapies.
Author: Erin Hertlein
Institution: The Ohio State University
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2268533348