Biology Reference
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node 9) that can be oxidized or covalently modified (see SR on node 7) in other ways
by pro-oxidants, resulting in the dissociation of Nrf2 from its grip (see the separation
of the 9-10 complex into nodes 7 and 8). The dissociation of Nrf2 and Keap1 is also
facilitated by the phosphorylation of Nrf2 at serine (S) and threonine (T) residues by
phosphotidylinositol-3-kinase (PI
3
K) (node 1), by protein kinase C (PKC) (node 2),
c-Jun NH2-terminal kinase (JNK) (node 3) and extracellular-signal-regulated kinase
(ERK) (see node 2). Once translocated into the nucleus, Nrf2 heterodimerizes with
MAF and binds to
antioxidant response element
(ARE) (see nodes 15, 16, and 19),
thereby activating the transcription of genes encoding many Phase II enzymes (see
nodes 20-24) that detoxify foreign chemicals or xenobiotics and reactive oxygen
species (ROS) and reactive nitrogen species (RNS). In short, chemical stress
activates the Nrf2 signaling pathway to induce enzymes that can remove the stressful
compounds, which may be regarded as an analog of
the Le Chatelier Principle
on the
intracellular metabolic level. As is well known in chemistry, the Le Chatelier
Principle states that, if a system in chemical equilibrium is disturbed, it tends to
change in such a way as to counter this disturbance. In another sense, the Nrf2
signaling pathway may be viewed as an intracellular version of
self-defense
mechanisms
that have been postulated to operate in the human body as a whole
and local tissue levels (Ji 1991, pp. 186-199). Frustrating any of the many processes
constituting self-defense mechanisms has been postulated to underlie all diseases,
including cancer. According to this so-called “frustrated self-defense mechanisms
(FSDM)” hypothesis of chemical carcinogenesis (Ji 1991, pp. 195-199), many
cancers may originate by frustrating some of the biochemical and cellular processes
underlying inflammation (including the cellular proliferation step in wound
healing). The FSDM hypothesis appears to have been amply supported by recent
findings (e.g., see Fig. 1 in Kundu and Suhr 2010).
The Nrf2 interaction network shown in Fig.
20.1
can be represented as an
interaction matrix (Table
20.1
). Although there are some ambiguities in assigning
node numbers (e.g., nodes 7 and 9 or nodes 8 and 10 may be combined into one
entity each), the matrix representation is sufficiently accurate in capturing the key
information embodied in the Nrf2 signaling network. The interaction matrix com-
bined with the diagram of the original signaling network allows us to identify all the
theoretically possible pathways that may be realized in the Nrf2 signaling network
in the cell under a given condition.
For example, any agent (e.g., diacylglycerol or intracellular Ca
2+
) that activates
PKC (node 2) can lead to the production of any one of the Phase II enzymes (nodes
20-24) passing through nodes 8, 15, and 19, or may get stuck in the middle of any
one of these pathways, thus generating a set of eight possible pathways that can be
engaged by the activation of node 2:
2-8-15-19-20, 2-8-15-19, 2-8-15, 2-8
2-8-15-19-21
2-8-15-19-22
2-8-15-19-23
2-8-15-19-24
