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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 82

B (PKB) plays a prominent role through the Forkhead nalling effects on redox signalling and there are redox sig-
box O 3a (FOXO3a) transcription factor, which acts nalling effects on Ca 2 + signalling.
by increasing the amount of manganese superoxide dis-
mutase (MnSOD) to provide greater protection against
ROS (Module 4: Figure FOXO control mechanisms). Ca 2 + signalling effects on redox signalling
An overactive redox signalling system may contribute One of the actions of Ca 2 + is to enhance redox signalling
to the increase in neuronal cell death that characterizes by interfering with the recovery of the oxidation-sensitive
Alzheimer’s disease (Module 12: Figure astrocyte-induced processes.Ca 2 + acts by turning down the thioredoxin sys-
neuronal death)and Down’s syndrome. tem by inhibiting the thioredoxin reductase that normally
switches off redox signalling.
Redox signalling and DNA damage
One of the major pathological consequences of excess ROS Redox signalling effects on Ca 2 + signalling
formation is DNA damage. When this damage occurs dur- There are numerous examples of redox signalling acting
ing the G 1 phase of the cell cycle, specific repair mechan- to enhance Ca 2 + signalling. For example, the two Ca 2 +
isms function to repair the damage and they also induce
the process of G 1 checkpoint signalling to DNA double- release channels ryanodine receptors (RYRs) and the InsP 3
receptors (InsP 3 Rs) can be activated by oxidation of key
strand breaks (DSBs) (Module 9: Figure G 1 checkpoint
signalling). cysteine residues. In the case of the latter, the oxidizing
agent thimerosal faithfully reproduces the Ca 2 + transi-
ents normally induced by sperm fusion during fertilization
Redox signalling in vascular homoeostasis
(Module 2: Figure thimerosal-induced Ca 2 + signalling).
Hydrogen peroxide (H 2 O 2 ) may function as an
Another example is that hydrogen peroxide (H 2 O 2 ) can
endothelium-derived hyperpolarizing factor (EDHF) that
markedly enhance Ca 2 + signalling by inhibiting the Src
diffuses across to relax neighbouring smooth muscle cells.
homology 2 (SH2) domain-containing protein tyrosine
This action may be particularly important in regulating the
phosphatase-1 (SHP-1), which normally acts to keep in
tone of cerebral arteries.
check the protein tyrosine phosphorylation cascade that
occurs during B cell receptor (BCR) activation (Module 2:
Redox signalling and gene transcription Figure ROS effects on Ca 2 + signalling). This is a reciprocal
The redox signalling pathway has been implicated in the interaction because it is the increase in Ca 2 + that activates
control of gene transcription, particularly with regard to the formation of H 2 O 2 through a Ca 2 + -dependent activ-
the activation of nuclear factor κB(NF-κB). Whether this ation of dual oxidase (DUOX). This is a good example of
activation is due to a direct modulation of the transcription the cross-talk that can exist between signalling pathways.
factor by messengers such as H 2 O 2 or indirectly through
activation of other signalling pathways remains to be de-
termined. Mitogen-activated protein kinase
A large number of other transcription factors [activat- (MAPK) signalling
ing protein 1 (AP-1), specificity protein 1 (SP1), c-Myb,
Overview
p53 and Egr-1] are redox-sensitive. Many of these have
The multifunctional mitogen-activated protein kinase
a highly conserved cysteine residue located within their
(MAPK) signalling system consists of separate pathways
DNA-binding domains that has to be reduced in order that function to control a number of different cellular pro-
for the factor to bind DNA (Module 4: Figure SRF and cesses such as gene transcription, metabolism, motility, cell
AP-1). In theory, therefore, such factors would be inhib- proliferation, apoptosis, synaptic plasticity and long-term
ited by oxidation. There is a nuclear redox factor 1 (Ref-1) memory. These different downstream effectors are activ-
that functions to control transcription by reducing this ated by the final MAPK components associated with the
cysteine. three main signalling pathways:
HDAC oxidation is an important mechanism used to
control chromatin remodelling and gene transcription. • Extracellular-signal-regulated kinase (ERK) pathway
• c-Jun N-terminal kinase (JNK) pathway
Redox factor 1 (Ref-1) • p38 pathway
Ref-1 plays a role in the nucleus to promote gene tran-
scription (Module 4: Figure SRF and AP-1) and to protect These different pathways are assembled by combining
cells against oxidative stress. There is a possibility that it components from an extensive mitogen-activated protein
might also have a function within the cytoplasm to reduce kinase (MAPK) signalling toolkit.
the Rac-1-regulated production of reactive oxygen species The mitogen-activated protein kinase (MAPK) sig-
(ROS). nalling properties such as their spatio-temporal control
mechanisms help to explain how they operate to regulate
Redox signalling and modulation of Ca 2 + so many cellular processes.
signalling The activity of the MAPK signalling pathway is reversed
There are reciprocal interactions operating between the by the mitogen-activated protein kinase (MAPK) phos-
redox and Ca 2 + signalling pathways. There are Ca 2 + sig- phatases.

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