Biomedical Engineering Reference
In-Depth Information
activation of specific mitogen-activated protein kinases (MAPKs) of which
JNK is a central component (20). Jun N-terminal kinase increases DNA
binding and gene transactivating activity of AP-1 by increasing the produc-
tion of c-Fos and by increasing the affinity of c-Jun for c-Fos. JNK also
phosphorylates Elk-1, which enhances c-Fos transcription (20) by binding
to the serum response element in its promoter. c-Jun transcriptional activa-
tion is mediated by a TRE that is bound by the transcriptional activator
ATF-2, either as a homodimer or as heterodimer with c-Jun. In this way,
c-Jun may autoregulate expression of its own gene. In addition, ATF-2 is
phosphorylated by JNK (19,20) leading to an increase in c-Jun expression.
B. Chromatin Remodeling
Alterations in the structure of chromatin are critical to the regulation of
gene expression (21). This chromatin structure is composed of nucleosomes,
which are particles consisting of
146 bp DNA associated with an octomer
of two molecules each of core histone proteins (H2A, H2B, H3, and H4). In
the resting cell, DNA is tightly compacted around these basic core histones,
excluding the binding of the enzyme RNA polymerase II, which activates
the formation of messenger RNA. This conformation of the chromatin
structure is described as closed and is associated with suppression of gene
expression. Acetylation of lysine residues on histones induces a relaxed
Chromatin structure allowing gene transcription to occur. Transcriptional
coactivators such as CREB binding protein (CBP) have intrinsic histone
acetyltransferase (HAT) activity, which is further activated by the binding
of transcription factors. Changes in the phosphorylation status of HATs
also affect their activity. Increased gene transcription is therefore associated
with an increase in histone acetylation, whereas hypoacetylation is corre-
lated with reduced transcription or gene silencing, which is regulated by his-
tone deacetylase (HDAC) (21,22).
III. HOW CORTICOSTEROIDS SWITCH OFF INFLAMMATION
We now have a much better understanding of the molecular mechanism by
which corticosteroids switch off the expression of inflammatory genes in dis-
eases such as asthma (23). Corticosteroids exert their effects by binding to a
cytoplasmic glucocorticoid receptor (GR), which is a 777 amino acid recep-
tor, a member of the nuclear hormone receptor superfamily. Glucocorticoid
receptors are expressed in almost all cell types and are modular in structure
(1,2). Thus, GR has several functional domains including a ligand-binding
domain (LBD), a DNA-binding domain, and two domains that are involved
in transactivation of genes, once binding to DNA has occurred via associa-
tion with other proteins (activation function, AF-1 and AF-2). The second
activation domain (AF-2) lies within the LBD. The inactive GR is bound to
