Inhibitor SourceBook™ Second Edition

NF-kB Activation Inhibitors
NF-kB, a eukaryotic transcription factor plays an
important role in inflammation, autoimmune response,
cell proliferation, and apoptosis by regulating the
expression of genes involved in these processes. It
consists of homo- or heterodimers of different subunits,
which belong to a family of Rel/NF-kB proteins. Five
different Rel proteins [p50, p52, p65 (Rel A), RelB, and
c-Rel] have been identified thus far. The most prevalent
activated form of NF-kB is a heterodimer of p50 or
p52 subunit and p65, which contains transactivation
domains necessary for gene induction. In unstimulated
cells, NF-kB is sequestered in the cytoplasm in an
inactive form, bound to regulatory proteins called
inhibitors of kB (IkB), of which IkBa and IkBb are
considered to be the most important. IkBa is associated
with transient NF-kB activation, whereas IkBb is
involved in sustained activation.
The activity of NF-kB is tightly regulated by interaction
with inhibitory IkB proteins. In most resting cells, NFkB
is sequestered in the cytoplasm in an inactive form
associated with inhibitory molecules, such as IkBa,
IkBb, IkBh, p105, and p100. This interaction blocks the
ability of NF-kB to bind to DNA and results in the NF-kB
complex being primarily localized to the cytoplasm due
to a strong nuclear export signal in IkBa.
Stimulation of cells by inflammatory cytokines, UV
light, or reactive oxygen species leads to the rapid
phosphorylation, ubiquitination, and ultimately
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proteolytic degradation of IkB, which frees NF-kB from
the NF-kB-IkB complex. NF-kB then translocates to the
nucleus where it binds to kB enhancer elements of proinflammatory
target genes to induce transcription. NFkB
is highly activated at sites of inflammation in diverse
diseases and induces transcription of pro-inflammatory
cytokines, chemokines, adhesion molecules, MMPs,
COX-2, and inducible nitric oxide (iNOS). Hence, NF-kB
has been considered as a desirable target for therapy in
various inflammatory diseases. In most cancer cells,
NF-kB is constitutively active and resides in the nucleus.
In some cases, this may be due to chronic stimulation
of the IKK pathway, while in others the gene encoding
IkBa may be defective. Such continuous nuclear NF-kB
activity not only protects cancer cells from apoptotic
cell death, but may even enhance their growth activity.
Designing antitumor agents to block NF-kB activity or
to increase sensitivity to conventional chemotherapy
may have great therapeutic value.
References:
Pande, V., and Ramos, M. J. 2005. Curr. Med. Chem. 12, 357.
Bouwnecster, T. et al. 2004. Nat. Cell Biol. 6, 97.
Marienfeld, R., et al. 2003. J. Biol. Chem. 278, 9852.
Ghosh, S., and Karin M. 2002. Cell 109, S8 .
Delhase, M., et al. 999. Science 284, 309.
Rahman, A., et al. 999. J. Immunol. 162, 5466.
Miyazawa, K., et al. 998. Am. J. Pathol. 152, 793.
Zandi, E., et al. 998. Science 281, 360.
Stancovski, I., and Baltimore, D. 997. Cell 91, 299.
Baldwin, A.S. Jr. 996. Annu. Rev. Immunol. 14, 649.
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