Schematic representation of signalling cascades and activation of NFKB and AP-1

The schematic representation of signalling cascades and activation of NF-κB and AP-1. The activation of NF-κB and AP-1 begin, in general, with stimulation of specific receptors at the cell surface and recruitment of adaptor proteins, which targets the external signal for specific transduction pathways controlled by various kinases. The NF-κB pathway converges upon a high-molecular mass multiprotein complex named IκB kinase (IKK) signalsome, which, in turn, promotes the phosphorylation of IκB. This targets IκB for ubiquitination and subsequent degradation by 26S proteasome. As a consequence, NF-κB is released and rapidly translocated to the nucleus where it binds to specific promoter regions of various genes. The IKK signalsome is activated by the NF-κB inducing kinase (NIK), which lies immediately upstream of IKKs in the NF-κB activation cascades. NIK mutants block TNF-α-and IL-1-induced NF-κB activation. Although the upstream signalling pathways that regulate NIK has not been clarified yet, there is some evidence to support the involvement of MAPK/ERK kinase kinase-1 (MEKK1), a kinase upstream of ERK as well as p38 MAPK. Many studies have revealed a close association between the MAPK activity and phosphorylation and degradation of IκB protein, which facilitates nuclear translocation and subsequent DNA binding of NF-κB in various cell systems. Recent reports showed that the NF-κB activation is also regulated by the Akt signaling pathway (,). Phosphatidylinositol 3-kinase (PI3-K) activates Akt/protein kinase B via phosphorylation by 3-phosphoinositide-dependent protein kinase-1 (PDK1). Genistein specifically inhibits Akt activity and Akt-mediated NF-κB activation. Epiegallocatechin gallate (EGCG) can block the activities of PI3-K and Akt. There is crosstalk between the Akt and NF-κB signaling pathways- Akt phosphorylation leads to activation of NF-κB by stimulating IκB kinase (IKK) activity. IKK is also a target of chemopreventive phytochemicals, including curcumin, resveratrol and EGCG (see text for details). AP-1 heterodimers are constitutively localized within the nucleus, and transactivation of AP-1 is achieved through phosphorylation of its activation domain by MAPK. The MAPK family proteins have been shown to play a key role in regulating AP-1 activation in various types of cells in culture. AP-1 represents a heterogenous set of dimeric proteins consisting of members of Jun, Fos, and ATF families. AP-1 mRNA expression is dependent on MAPKs: ERK1/2 phosphorylates Elk-1, JNK phosphorylates ATF-2 and c-Jun in c-fos and c-jun induction, respectively, while p38 phosphorylates both Elk-1 and ATF-2. c-Fos and c-Jun form heterodimers and bind to AP-1 response element in the promoter of target genes. The target molecule/event blocked/inactivated by chemopreventive phytochemicals is marked with a symbol (⦸).

Publication

Transcription Factors in the Cellular Signaling Network as Prime Targets of Chemopreventive Phytochemicals. (2004) Young-Joon Surh. Cancer Res Treat. 2004 Oct;36(5):275-286. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions