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NF-kB transcription factor is a pleiotrophic mediator of inducible and tissue specific gene control. In the 20 years following its discovery, the structure–function relationships of regulatory NF-kB complexes have been revealed and extensively reviewed during these years. In non-stimulated cells, NF-kB complexes are trapped in the cytoplasm via the binding to the inhibitory IkB proteins (IkBa, IkBb, IkBg, IkBe, and Bcl3). Stimulation, either external or internal, phosphorylates IkB proteins which are then ubiquitinated and broken down in the proteasomes. Subsequently, the NF-kB complex is translocated to the nucleus where it activates the transcription of a number of genes, especially inflammatory genes. This is the basic functional mechanism of the NF-kB transcription factor. There are numerous variations especially in the signaling pathways upstream of the NF-kB complex, but also in the downstream targets and transcriptional regulation. The major protein kinases activating NF-kB complexes are the IKKs (IkB kinases a and b) and NIK (NF-kBinducing kinase), but IKK-independent pathways also exist, as well as canonical and non-canonical pathways with different NF-kB components. Furthermore, IKKa and IKKb kinases can be integrated with distinct signaling pathways. NEMO, an essential NF-kB modulator and regulatory subunit of the IkB kinase (IKK) complex, regulates the activation of IKK kinase complex. The role of the NEMO signaling cascade is especially important in genotoxic stress.

NF-kB system is a cytoplasmic sensor responding not only to immune attacks, but also to a variety of external and internal danger signals, such as oxidative stress, hypoxia, and genotoxic stress. The efficiency of the NF-kB system is not based on the protein levels of the NFkB components in cytoplasm but rather on the translocation of protein components to nuclei and the efficiency of transcriptional regulation, e.g. via protein acetylation. There are several other inhibitors, in addition to the IkB proteins, such as A20. These inhibitors provide another layer of complexity to the feedback regulation of NF-kB system.

In the case of age-related signaling, it is also known that IKKb activation can prevent the functioning of FoxO3, similarly as the insulin/PI3K pathway. Furthermore, IKKb has been shown to down-regulate MAP kinase signaling and as well stabilizing cytokine and chemokine mRNAs. This crosstalk is required to balance NF-kB signaling and other signaling networks. HMGB1 is a secreted DNA-binding cytokine-like protein that provides an elegant reporting system from tissue damages. HMGB1 interacts with NF-kB complexes but this interaction is dependent on the presence of Rel components within the complex. HMGB1 binding increases the transactivation efficiency of NF-kB complexes. In general, HMGB1 seems to provide an effective, versatile amplifier of NF-kB signaling in inflammation. HMGB1 is expressed in the nuclei of several cell types, in fact the highest levels are found in monocytes. Its expression is significantly increased in several diseases, especially those which involve inflammation, such as Alzheimer’s disease. Age-related progressive accumulation of cellular damages, ‘‘garbage-can hypothesis’’, should increase apoptosis in mammalian tissues. Replicative senescence in vitro is associated with an increase in resistance to apoptosis. Interestingly, the master of inflammation, NF-kB signaling, is also a key player in anti-apoptotic signaling. For instance, NF-kB signaling activates the expression of c-FLIP, Bcl-xL, c-IAP1, c-IAP2, and XIAP proteins, all well-known inhibitors of apoptosis (IAPs). NF-kB signaling is also able to inhibit the apoptotic signaling by inhibiting the function of c-Jun N-terminal kinase (JNK), a well-known kinase mediating apoptotic signals. This NF-kB regulation is important since reactive oxygen species (ROS) activate the upstream kinases of JNK during oxidative stress and thus via JNK inhibition, NF-kB signaling can inhibit apoptosis and combat the effects of oxidative stress.