Biomedical Engineering Reference
In-Depth Information
regulate the interaction of p65 with selected coactivators or corepressors, leading to
changes in its transcriptional activity [39-41].
Kinase redundancy in the phosphorylation of specific sites in p65 is frequently
observed; however, the kinases involved are often induced by distinct stimuli or in
a cell-type-specific manner. For example, serine 276 of p65 is phosphorylated by
PKA
c
in response to LPS or by MSK1 after TNF-
α
stimulation. Similarly, serine
536 is phosphorylated by either IKK
mediates this phosphorylation
when monocytes or macrophages are stimulated with LPS [18], when human hepatic
stellate cells are triggered by CD40 [42], or when T cells are stimulated with
CD3/CD28 [43]. Conversely, IKK
α
or IKK
β
. IKK
β
α
, but not IKK
β
, phosphorylates serine 536 in
response to ligand activation of the lymphotoxin
receptor signaling pathway [21]
or after stimulation with the Tax oncoprotein of human T-leukemia virus (HTLV)-1
[44]. However, both IKK
β
α
and IKK
β
are involved in the phosphorylation of serine
536 after stimulation with TNF-
or IL-1 [19,22].
How phosphorylation specificity is achieved when these different signaling
pathways are activated is not well understood. Different patterns of p65 phospho-
rylation could certainly influence the recruitment and divestment of different tran-
scriptional cofactors, which in turn could mediate distinct profiles of gene expression.
Precedence for such a scenario is found with steroid receptor coactivator 3 (SRC-3).
Phosphorylation of SRC-3 at different sites differentially regulates the interaction
with downstream transcriptional activators and coactivators and in this way integrates
diverse signaling pathways [45].
α
5.3
NF-
κ
B AND ACETYLATION
The assembly of NF-
B with different coactivator and corepressor proteins is crucial
in orchestrating its ultimate biological effects. For example, NF-
κ
B can associate
with a series of different coactivators such as p300/CBP, p300/CBP-associated factor
(PCAF), and members of the p160 nuclear receptor coactivator family, including
SRC-1 and -3, each of which exhibits intrinsic histone acetyltransferase (HAT)
activity [46,47]. The interaction of the p65 subunit of NF-
κ
B with either CBP or
p300 sharply increases the transcriptional activity of the NF-
κ
B complex through
both modification of chromatin structure [48,49,50,51] and, as discussed in greater
detail below, the direct acetylation of p65 [52]. Similarly, SRC-1 can also function
as a coactivator with NF-
κ
B, but in this case, binding is mediated by the p50 subunit
[48,53]. Another p160 family member, SRC-3, functions as an NF-
κ
B coactivator
and intriguingly is phosphorylated by the IKKs [45,54]. The arginine methyltrans-
ferase CARM1/PRMT4 is a novel transcriptional coactivator of NF-
κ
κ
B that acts
synergistically with the p300/CBP and SRC-2 acetyltransferases [55].
In addition to its selective interaction with various coactivators, NF-
B also
can physically associate with a family of corepressors, including specific HDACs
[14,52,56,57]. Recruitment of these HDACs to the enhancers of various NF-
κ
B
target genes can lead to modification of the surrounding histone tails, promoting
transcriptionally repressive changes in chromatin structure. In addition, HDAC3
promotes the deacetylation of p65, which diminishes DNA binding and transcrip-
tional activity and increases binding to I
κ
κ
B
α
[52]. Similarly, sirtuin (silent mating
