NF-κB and AP-1 Connection: Mechanism of NF-κB-Dependent Regulation of AP-1 Activity

Abstract

Nuclear factor B (NF-B) and activator protein 1 (AP-1) are key transcription factors that orchestrate expression of many genes involved in inflammation, embryonic development, lymphoid differentiation, oncogenesis, and apoptosis (48, 62). NF-B and AP-1 activities are induced by a plethora of physiological and environmental stimuli (5, 51).The activity of NF-B is regulated by its interaction with the family of NF-B inhibitors known as IB, which results in the formation of inactive NF-B-IB complexes in the cytoplasm (3,4,60). In response to various stimuli, the IB kinase complex (IKK) then phosphorylates the IB bound to the NF-B complexes as substrates (8,36,45,47). The subsequent proteasome-mediated degradation of IB exposes the nuclear localization signal (NLS) of NF-B, which releases the NF-B proteins to be translocated to the nucleus, where they regulate the transcription of specific genes (5, 48).AP-1 is a group of basic leucine zipper (bZIP) transcription factors consisting of the Fos (c-Fos, FosB, Fra1, and Fra2) and Jun (c-Jun, JunB, and JunD) families (54, 62). The predominant forms of AP-1 in most cells are Fos/Jun heterodimers which have a high affinity for binding to an AP-1 site, whereas Jun/Jun homodimers bind to the AP-1 site with low affinity (54,62). A number of studies have shown that serum and growth factors that induce AP-1 do so by activating the extracellular signal-regulated kinase (ERK) subgroup of mitogen-activated protein kinases (MAPKs) (9, 27, 55). These activated members of MAPKs translocate to the nucleus to phosphorylate and thereby transcriptionally activate a subfamily of ETS domain transcription factors known as ternary complex factors (TCFs) that bind to fos promoters (9,27,55,65,80). fos, fosB, and other members of the AP-1 family of transcription factors are mainly regulated at their transcription through serum responsive elements (SREs) in their promoters (57,76). For example, the regulation of c-fos expression is controlled by Elk, a member of TCFs that associates with the serum response factor (SRF) (11,28,49). The elk-1 gene encodes two spliced variants: elk-1 and an alternatively spliced variant known as ⌬elk-1, which is missing the SRF interaction domain and part of the elk-1 DNA binding domain (61). The ⌬Elk-1protein cannot form an SRF-dependent ternary complex with SRE to activate fos transcription (61). However, a variety of experiments have shown that Elk-1 proteins play a central role in the response of cells to many extracellular signals and control the expression of genes involved in cell cycle progression, differentiation, and apoptosis (62, 75). The mechanism by which Elk-1 activates transcription in response to various stimuli has been extensively studied; however, less is known about the regulation of elk-1 gene expression itself.Even though NF-B and AP-1 transcription factors are regulated by different mechanisms, they appear to be activated simultaneously by the same multitude of stimuli (1,19,37,43,71,78). A number of reports also showed that these transcrip...

Visualization of AP-1–NF-κB ternary complexes in living cells by using a BiFC-based FRET

“…NF-B also cross-talks with other families of transcription factors, such as AP-1 (28,29). These cross-talks can occur through the binding of NF-B and AP-1 to composite binding sites in the regulatory regions of target genes, such as cytokines IL-1, IL-8, and TNF␣ (29), or through their mutual regulation at the transcriptional level (28).…”

“…NF-B also cross-talks with other families of transcription factors, such as AP-1 (28,29). These cross-talks can occur through the binding of NF-B and AP-1 to composite binding sites in the regulatory regions of target genes, such as cytokines IL-1, IL-8, and TNF␣ (29), or through their mutual regulation at the transcriptional level (28). In addition, the physical interaction between the NF-B subunit p65 and c-Jun or c-Fos at both endogenous and exogenous levels also has been observed previously by us and others (12,30).…”

Plant Pectin: A Potential Source for Cancer Suppression

“…Recently, Chen et al (2006) have shown that when LPS-activated macrophages are Science Publications AJPT incubated with 90% esterified pectin they inhibit the activation and binding of Nf-kB and AP-1 transcriptional factors to the respective promoter nucleotide sequences and down-regulates the mRNA and protein expression of iNOS and COX2. The activation of transcriptional factors Nf-kB and AP-1 are known to be involved in the pathogenesis of numerous cancers (Fujioka et al, 2004). It is also known that overxpression of iNOS and COX2 by AP-1 and Nf-kB, respectively, is involved in the pathogenesis of colon cancer (Watanabe et al, 2000).…”

When nutrition interacts with osteoblast function: molecular mechanisms of polyphenols

“…AP-1 and NF-kB transcription factors involved in MAPK signalling pathways are regulated by different mechanisms, but it appears that they could be activated simultaneously by the same agents. Thus these transcription factors work together and may modulate the activity of each other (75) .…”

“…AP-1 and NF-kB are also implicated in the regulation of genes involved in many important biological processes in osteoblasts as well as osteoclasts. It was claimed that AP-1 can be induced by both oxidant and antioxidant conditions and it is primarily transcriptionally regulated (74,75) . Activating transcription factor, Jun and Fos are the part of the dimeric transcription factor complex AP-1 and are known activators of proliferation, differentiation and apoptosis-related genes (76) .…”