Biomedical Engineering Reference
In-Depth Information
, IL-1, and LPS. These findings bolster the notion that
other kinases can phosphorylate serine 10 [101,102]. MSK1 and PKA, which phos-
phorylate key serine residues of p65, may also function as histone H3 serine 10
kinases in the presence of different stimuli [103,104]. In addition, IKK
respond normally to TNF-
α
β
could
represent an additional histone H3 serine 10 kinase. IKK
effectively phosphorylates
histone H3
in vitro
and is recruited to the promoter of some NF-
β
B target genes
after activation [61]. Indeed, it is interesting to consider the possibility that different
kinases are preferentially recruited to the promoters of different NF-
κ
B target genes
in a stimulus-specific or cell-context-specific manner. Such recruitment of these
enzymes could provide an additional level of control contributing to selective acti-
vation of different genes in response to different extracellular stimuli.
κ
5.6
CONCLUSIONS
Our understanding of the multilayered regulation of NF-
κ
B is expanding quite
rapidly. Control of NF-
κ
B is not limited to the early cytoplasmic events that lead
to I
B into the nucleus. Rather, the action
of this transcription factor is also regulated by later events involving the posttrans-
lational phosphorylation and acetylation of NF-
κ
B
α
degradation and translocation of NF-
κ
B itself and the modification of
histones surrounding cellular genes whose expression is induced by NF-
κ
B. The
recognition that these nuclear posttranslational events shape the strength and duration
of the NF-
κ
κ
B transcriptional response has opened an exciting new chapter in NF-
κ
B
biology (
Figure 5.3
).
It is now clear that both the phosphorylation and acetylation of the p65 subunit
of NF-
κ
B are required to generate a fully active NF-
κ
B complex. In the absence of
these modifications, NF-
B displays significantly impaired transcriptional activity.
Emerging evidence now suggests that these modifications can occur in an ordered
manner with phosphorylation triggering subsequent acetylation of p65 through
recruitment of acetyltransferases such as p300 and CBP. The p65 subunit might also
be regulated by less well-studied posttranslational modifications such as ubiquity-
lation and methylation [105]. The composite effects of these modifications are a
biologically rich area for future NF-
κ
B research.
However, nuclear posttranslational changes are not limited to NF-
κ
B. Indeed,
posttranslational modifications of histones are associated with changes in chromatin
structure that influence the expression of NF-
κ
B responsive genes. As we have
discussed, the phosphorylation and acetylation of histone tails in chromatin sur-
rounding NF-
κ
B target genes can markedly enhance their transcription. Similarly,
methylation of certain arginine or lysine residues in the histones can promote acti-
vation of NF-
κ
B target genes [55,85,88], while methylation at other sites is associ-
ated with transcriptional repression. Each of these different posttranslational modi-
fications of the histone tails creates a specific “mark” in the chromatin that may
regulate the binding or divestment of specific cofactors, which combine to shape the
ultimate transcriptional response. In aggregate, these epigenetic modifications have
been termed the “histone code” [106,107]. Of note, like the modification of p65,
this code is often constructed sequentially. For example, phosphorylation of serine
κ
