Biomedical Engineering Reference
In-Depth Information
ubiquitously expressed TF that plays a critical role in regulating inducible gene
expression in inl ammatory responses (Baldwin 1996, Barnes and Karin 1997).
Dif erent forms of NF-κB activate various sets of target genes to exert its diversii ed
functions. NF-κB increases gene expression of many cytokines, enzymes, and
adhesion molecules in acute and chronic inl ammatory conditions. In chronic
inl ammatory diseases, adhesion molecules recruit inl ammatory cells from the
circulation to the site of inl ammation and NF-κB regulates the expression of these
genes that encode adhesion molecules such as intercellular adhesion molecule 1
(ICAM-1), E-selectin, integrin, and VCAM-1. Interestingly, certain viruses use
NF-κB activation to enhance viral replication, host cell survival, and evasion of
immune responses. Simultaneously, it also evokes the adhesion molecule gene
upregulation and results in specii c leukocyte migration into the site of viral
infection (Hiscott
et al.
2001). Importantly, it has been coni rmed that most but not
all of these adhesion molecule genes possess at least one or more NF-κB binding
sites in their promoter regions, indicating the importance of NF-κB activation in
the modulation of expression of these genes (Voraberger
et al.
1991, Schindler and
Baichwal 1994, Wang
et al.
1999, Melotti
et al.
2001).
In resting cells, NF-κB is normally sequestered in the cytoplasm through its
interaction with the IκB (inhibitor of NF-κB) family of inhibitory proteins. A major
advance in the understanding of NF-κB regulation came with the identii cation
of the multisubunit IKK kinase complex, which contains two catalytic subunits,
IKK-α and IKK-β, and the regulatory subunit IKK-γ. h e predominant form of
the IKK complex is an IKK-α/IKK-β heterodimer associated with IKK-γ, and
this association is mediated by the interaction of IKK-β and IKK-γ. IKK-γ is
not a kinase per se but is absolutely essential for NF-κB activation by multiple
activators. Since the identii cation of the IKK complex, attention was focused on
the upstream kinases of dif erent signal transduction pathways and how these
pathways converge on the IKK complex. h ese kinases include NF-κB-inducing
kinase (NIK), mitogen-activated protein kinase/extracellular signal-regulated
kinase kinase 1 (MEKK1), TGF-β-activated kinase (TAK1), protein kinase R
(PKR), PKC, PI3K-Akt (or PKB), and mixed-lineage kinase 3 (MLK3). Once
activated, IKK-β becomes autophosphorylated at a carboxyl terminal serine
cluster, which decreases IKK activity and prevents prolonged NF-κB activation by
negative autoregulation (Hacker and Karin 2006). In response to external stimuli,
IκB proteins undergo rapid phosphorylation by IKK complex on specii c serine
residues. Phosphorylation of IκBα on serines 32 and 36, and of IκBβ on serines
19 and 23 facilitates their ubiquitination on neighboring lysine residues, thereby
targeting these proteins for rapid degradation by the proteosome (Baldwin 1996,
Hacker and Karin 2006). Following the degradation of IκB, NF-κB is released and
is free to translocate to the nucleus and to activate target inl ammatory genes by
binding to the specii c sequences in the promoters.
