Biomedical Engineering Reference
In-Depth Information
consideration when NF-
B blockade is considered in combination with standard
chemotherapy, which itself compromises the immune system and exacerbates tissue
damage [188]. Furthermore, NF-
κ
B inhibition may in fact be a “double-edged sword,”
as in the presence of a carcinogen, and perhaps even under chemotherapeutic poison-
ing, NF-
κ
κ
B inhibition may facilitate, rather than prevent, tumor development [194].
4.9
SYNOPSIS
An intense research effort during the past decade has generated a detailed scheme
of the signaling pathways regulating the activation of NF-
B (
Figures 4.1
,
4.2
,
and
κ
at multiple steps and the coupling of this modification to signal-induced phospho-
rylation. The canonical pathway involves ubiquitin-mediated activation of the
classical IKK complex, which then targets the three NF-
κ
B inhibitory proteins
(I
TrCP-mediated ubiquitination and proteasomal
destruction. Stimulation of the alternative pathway by a subset of NF-
κ
B
α, β,
and
ε
) and p105 for
β
κ
B agonists
targets p100 for
TrCP-mediated processing, generating p52-RelB heterodimers.
Recent genetic data have highlighted the important role for removal of K63-linked
ubiquitin in shutting off NF-
β
B activity and impairment of this control in cylin-
dromatosis results in increased NF-
κ
B activation, which may be important in tumor
progression. K48-linked ubiquitination has also been shown to be important in
downregulating NF-
κ
κ
B activity by promoting proteasome-mediated proteolysis of
p65 and cRel.
Several key questions remain regarding the role of ubiquitination in NF-
κ
B
activation:
•
How many NF-
B agonists utililize TRAF-mediated ubiquitination to
activate IKK and also what is the structural basis for ubiquitination-
dependent activation of IKK?
κ
•
Where are I
B ubiquitination and proteolysis taking place? Some exper-
imental evidence suggests that ubiquitination and proteolysis of both I
κ
B
and p100 are controlled by a cytoplasmic/nuclear shuttling mechanism.
κ
•
Are there any specific proteasome adaptor molecules that ensure degra-
dation of I
κ
Bs, while protecting associated NF-
κ
B from proteolysis by
the proteasome?
•
What are the E3s involved in controlling the ubiquitination and proteolysis
of Rel subunits in the nucleus?
•
How is the expression and activity of the key ubiquitin system enzymes
involved in NF-
TrCP, Ubc13/Uev1a, CYLD, and
A20) controlled and is the proteasome itself regulated?
κ
B activation (i.e.,
β
•
What is the mechanism by which phosphorylated and ubiquitinated I
κ
B
is protected from proteasomal degradation in gut epithelial cells?
B research is entering its third decade, the regulation and functions of
ubiquitination are still likely to remain a major focus, and the answers to many of
these questions should not be long in coming.
As NF-
κ
