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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 81

mitochondrial membrane potential and contributes to the the mitochondrial permeability transition pore (MTP) to
inhibition of apoptosis by regulating the nitrosylation induce apoptosis. As so many key signalling functions are
levels of the mitochondrial caspases. Activation of the being influenced, it is not surprising to find that there is a
FAS signalling system can increase the activity of Trx2, role for redox signalling in many cellular processes:
which switches the balance towards the more active de-
nitrosylated form of the caspases. • redox signalling in proliferation and cancer
Expression of the thioredoxin-interacting protein • redox signalling in apoptosis
(Txnip), which binds to Trx and inhibits its participation • redox signalling and DNA damage
in the denitrosylation reaction, is reduced in schizophrenia • redox signalling in vascular homoeostasis
and thus contributes to the increase in redox signalling in • redox signalling and gene transcription
schizophrenia (Module 12: Figure schizophrenia). • redox signalling and modulation of Ca 2 + signalling
• redox signalling in schizophrenia
Thioredoxin reductase (TrxR)
Thioredoxin reductase (TrxR) together with thioredoxin Redox signalling in proliferation and cancer
(Trx) is an important oxidoreductase system that has a One of the main actions of redox signalling is to con-
significant role in regulating the redox state (Module 2: trol growth. During the action of many growth factors
Figure recovery of protein oxidation). there is an increase in the production of hydrogen peroxide
Trx reductase is unusual in that it contains seleno- (H 2 O 2 )(Module 2: Figure plasma membrane ROS form-
cysteine (SeCys) located in the C-terminal active site, ation), which facilitates growth factor signalling by in-
which has a highly conserved -Gly-Cys-SeCys-Gly- se- hibiting tyrosine phosphatases and the tumour suppressor
quence. The N-terminal region contains flavin--adenine phosphatase and tensin homologue deleted on chromo-
dinucleotide (FAD). The enzyme operates by transferring some 10 (PTEN). The latter inhibits the hydrolysis of
electrons from NADPH to FAD and then on to the active PtdIns3,4,5P 3 (PIP 3 ), which functions in cell migration,
site in the C-terminus. proliferation and survival. H 2 O 2 inactivates PTEN by in-
The level of Trx reductase is greatly increased in vari- ducing a disulphide bond to form between Cys-124 in the
ous tumour cells, where it may play an important role active site and Cys-71. This disulphide is specifically re-
in inhibiting apoptosis by regulating the activity of Trx versed by thioredoxin. A reversible inactivation of PTEN
that inhibits apoptosis signal-regulating kinase 1 (ASK1). may thus contribute to the accumulation of PIP 3 ,which
An enhanced level of TrxR may prevent apoptosis by en- will thus set up a positive-feedback loop, since the forma-
suring that the Trx remains reduced to ensure that ASK1 tion of PIP 3 is responsible for stimulating the production
remains inactive. of H 2 O 2 .
The ability of this thioredoxin system to reverse redox Many cancer cells are known to use ROS to control
signalling is inhibited by Ca 2 + , which acts to convert a their proliferation. There are five human homologues of
large proportion of the reduced Trx-(SH) 2 into its ox- Nox1. When Nox1 is overexpressed in fibroblasts, there
idized form. Such an action would enhance the growth- is an increase in proliferation and tumour formation. The
promoting activity of the redox signalling system. addition of antioxidants can reduce the growth of cancer
Thioredoxin-2 (Trx-2) is a mitochondria-specific mem- cells.
ber of the Trx family. It functions to regulate the mitochon- Many cancer cells, like a number of stem cells, have en-
drial membrane potential and contributes to the inhibition hanced ROS defences in the form of elevated levels of GSH
of apoptosis. and thioredoxin, which make them particularly resistant to
apoptosis. Thioredoxin may also play a role in increasing
Glutathione reductase the expression of the hypoxia-inducible factor 1α (HIF-
Glutathione reductase is responsible for converting oxid- 1α), resulting in an increase in vascular endothelial growth
ized GSSG back into the reduced GSH (Module 2: Figure factor (VEGF) and tumour angiogenesis.
recovery of protein oxidation):
Redox signalling in apoptosis
GSSG + NADPH + H + → 2GSH + NADP + In addition to playing a role in cell proliferation, there is a
darker side to reactive oxygen species (ROS) in that they
Oxidation-sensitive processes can also activate apoptosis. One of the actions of redox
The redox signalling pathway acts to regulate a vari- signalling is that it contributes to Ca 2 + -induced apop-
ety of oxidation-sensitive processes (Module 2: Figure tosis at the level of the mitochondria. The uptake of Ca 2 +
plasma membrane ROS formation). The cellular pro- and the resulting increase in ROS formation act syner-
teins that are sensitive to oxidation are those that contain gistically to open the mitochondrial permeability trans-
hyperreactive cysteine residues. One of the main func- ition pore (MTP) (Module 5: Figure mitochondrial Ca 2 +
tions of redox signalling is to modulate the activity of signalling). ROS can also increase apoptosis by stimulat-
other signalling systems that contain protein compon- ing the acidic sphingomyelinases (SMases) that produce
ents with such hyperreactive cysteine residues, e.g. Ca 2 + - ceramide (Module 2: Figure sphingomyelin signalling).
releasing channels [inositol 1,4,5-trisphosphate receptors Cells have different ways of suppressing this ROS-
(InsP 3 Rs) and ryanodine receptors (RYRs)], transcription induced apoptosis. One mechanism is carried out by
factors, protein tyrosine phosphatases and by activating PtdIns 3-kinase signalling during which protein kinase

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