Biomedical Engineering Reference
In-Depth Information
endogenous NF-
κ
B inhibitors other than I
κ
B family members, as these are discussed
at length in
Chapters 2
and
4
.
In addition to endogenous factors that modify NF-
κ
B, many viruses and bacteria
express proteins — exogenous NF-
B signaling to
thwart the host immune response. Although these proteins may not be ideal for
clinical development, they have provided new insights into NF-
κ
B inhibitors — that inhibit NF-
κ
κ
B regulation, and
small molecule inhibitors of NF-
B signaling have already been derived based on
sequences present in these viral and bacterial proteins.
κ
10.2.1
E
NDOGENOUS
I
NHIBITION
OF
NF-
κ
B S
IGNALING
Several tumor suppressor genes have been reported to regulate NF-
B activity. The
tumor suppressor gene adenosine diphosphate (ADP) ribosylation factor 1 (ARF)
has been reported to induce the phosphorylation of thr505 in the transactivation
domain (TAD) of p65, resulting in recruitment of histone deacetylase-1 (HDAC1)
κ
and inhibition of NF-
κ
B activity (
Chapter 5
) [5,6]. The tumor suppressor gene ING4
was shown to physically interact with p65 in the nucleus, forming a transcriptional
complex in which NF-
B-induced gene expression is downregulated, leading to
inhibition of angiogenesis in a brain tumor model [7]. Finally, it was suggested that
p53 and NF-
κ
B control each other's ability to express their target genes — a
regulatory “transcriptional crosstalk.” This effect was dependent on the relative level
of p53 and NF-
κ
B, and it was proposed that competition for a limiting pool of
CBP/p300 complexes underlies this regulatory balance [8
,
9].
NF-
κ
B signaling has become a standard example of how ubiquitination and
deubiquitination play a role in the activation and deactivation of signaling pathways.
As discussed in Chapter 4, it is now apparent that protein-ubiquitination does not
always lead to degradation of the ubiquitinated protein but that certain proteins
depend on ubiquitination for localization or activity. Several proteins involved in
NF-
κ
B signaling (e.g., tumor necrosis factor-receptor 1 [TNF-RI], tumor necrosis
factor receptor associated factor 2 [TRAF2], receptor interacting protein [RIP],
nuclear factor kappa B essential modifier [NEMO], and inhibitor of kappa B kinase
β
κ
[IKK
β
]) are ubiquitinated, although the functional implications of this are largely
unclear. Cylindromatosis (CYLD) and A20, as discussed in Chapter 4, act as endog-
enous negative regulators of NF-
κ
B, signaling by modifying the ubiquitination of
these pathway components.
Sumoylation can also affect NF-
B activity at different levels [10]. Sumoylation
of a small fraction of NEMO has been shown to govern its nuclear localization and
prevent it from shuttling to the cytoplasm, as discussed in Chapters 2 and 4. More
recently, it has been reported that the sumoylation of CBP/p300 enables the binding
of sirtuin (silent mating type information regulation 2 homolog) 1 (SIRT1) to p300,
thereby repressing p300. SIRT1, a member of the nicotinamide adenosinedinucle-
otide (NAD)-dependent deacetylases, represses several transcription factors, includ-
ing NF-
κ
κ
B. As CBP/p300 is a limiting cofactor for the transcriptional activity of
NF-
B, it was suggested that desumoylation of CBP/p300 leads to a relieving of
p300-repression by SIRT1, which in turn could lead to enhanced transcription
mediated by NF-
κ
κ
B (Chapter 5) [11].
