NF‐κB regulation: the nuclear response

Abstract

Nuclear factor κB (NF-κB) is an inducible transcription factor that tightly regulates the expression of a large cohort of genes. As a key component of the cellular machinery NF-κB is involved in a wide range of biological processes including innate and adaptive immunity, inflammation, cellular stress responses, cell adhesion, apoptosis and proliferation. Appropriate regulation of NF-κB is critical for the proper function and survival of the cell. Aberrant NF-κB activity has now been implicated in the pathogenesis of several diseases ranging from inflammatory bowel disease to autoimmune conditions such as rheumatoid arthritis. Systems governing NF-κB activity are complex and there is an increased understanding of the importance of nuclear events in regulating NF-κB's activities as a transcription factor. A number of novel nuclear regulators of NF-κB such as IκB-ζ and PDZ and LIM domain 2 (PDLIM2) have now been identified, adding another layer to the mechanics of NF-κB regulation. Further insight into the functions of these molecules raises the prospect for better understanding and rational design of therapeutics for several important diseases.

NF-κB Signaling: A Tale of Two Pathways in Skeletal Myogenesis

“…Conversely, de phosphorylation of Ser-536 by the phosphatase WIP1 was recently shown to inhibit N F -kB transactivation function (29). The p65 subunit undergoes further posttranslational modifications that include acetylation at residues Lys-122, Lys-218, and Lys-310, mediated by p300/CBP and other proteins with histone acetyl transferase (HAT) activity to enhance p65 transcriptional activity (95). Furthermore, p65 activity can be negatively regulated through SOCS-1-dependent ubiquitination of residues 220 and 335, leading to p65 proteasomal degradation (58,127).…”

“…RelA/p65 (here after referred to as p65) can be phosphorylated on nu merous amino acids including Ser-276, Ser-529, and Ser-536. These modifications are directed by various kinases such as protein kinase A (PKA), mitogen-and stressactivated protein kinase 1 (MSK1), Tank binding kinase 1 (TBK1), and casein kinase 2 (CK2) (19,95,111). Ser-311 is also phosphorylated in vitro directly by the £-isoform of protein kinase C and in vivo through tumor necrosis factor (TNF)-a stimulation (43).…”

Therapeutic Potential of the Proteasome Inhibitor Bortezomib on Titanium Particle-Induced Inflammation in a Murine Model

“…It is well known that NF-κB is one of the most important mediators related to inflammation. The elevated expression of NF-κB is considered to be a fundamental event in many acute and chronic inflammatory disorders [18,19], so significant attention has been focused on the development of anti-inflammatory drugs targeting NF-κB [20]. In this study, we found that the expression of NF-κB p65 markedly increased in pouches of the Ti group compared with those of the PBS group on both day 2 and day 7, while a significant decrease in the expression levels of the protective mediator IκBα was observed in pouches of the Ti group compared with levels in the PBS group.…”

Transcriptional Regulation of Gene Expression by microRNAs as Endogenous Decoys of Transcription Factors

“…However, there is a possibility that miR-939 can also bind to p65, which merits future studies to verify. Additionally, NF-κB has been linked to a wide variety of signaling mediators such as JNK, AP-1 and MAPK, aside from Bcl-xL [44,45]. It would be important to clarify in the future whether these other factors are also regulated by miR-939 through decoy-like action on NF-κB.…”