Chemistry Reference
In-Depth Information
6.2 Signal Transduction Pathways Affected
by Metal Compounds
by serine/threonine phosphorylation by MAPK kinase
kinases (MAPKKK). Additional protein kinases and
members of the Ras and Rho families of small GTPases
may also participate upstream of the MAPKKKs. Once
activated, MAPKs can alter the activity of target tran-
scription factors and transcriptional coregulators by
phosphorylation, resulting in changes in the expres-
sion of genes that mediate cell growth, proliferation,
differentiation, apoptosis, and transformation (Schaef-
fer and Weber, 1999). Studies have shown that metals,
such as As, Cd, Co, Cr, and Ni, can activate MAPK
pathways.
6.2.1 ROS
Reactive oxygen species (ROS) are highly reactive
molecules with unpaired electrons formed during oxi-
dative metabolism. They include the superoxide anion
(O
2
−
), the hydroxyl radical (OH), and hydrogen perox-
ide (H
2
O
2
) (Halliwell, 1981; Halliwell and Gutteridge,
1984). They are continuously generated and eliminated
in biological systems and play important roles in the
regulation of cell proliferation, apoptosis, transforma-
tion, and senescence. Cells are able to defend against
ROS stress with antioxidant scavengers (i.e., ascor-
bate, glutathione, and thioredoxin), and antioxidant
enzymes (i.e., superoxide dismutase [SOD], catalase,
glutathione peroxidase, and thioredoxin reductase).
With their antioxidant defense systems, cells can adapt
to low physiological concentration of ROS (Storey,
1996). However, ROS can cause oxidative damage to
cellular macromolecules, including DNA, proteins,
and lipids, when generation of these potentially harm-
ful species exceeds cellular antioxidant defenses. ROS
play important roles in the initiation of cellular injury
that can lead to the development of cancer (Toyokuni,
1998; Toyokuni
et al.
, 1995). One of the most important
ways that ROS may cause cancer is by acting as signal
transduction messengers to activate signaling path-
ways, such as MAPK, PI3K, NF-
6.2.3 PI3K/Akt
The phosphatidylinositol-3 kinase (PI3K) pathways
are involved in regulating cell growth, differentiation,
and apoptosis (Fresno Vara
et al.
, 2004). PI3Ks constitute
a lipid kinase family characterized by their abilities to
phosphorylate phosphoinositides (PIPs) at the 3'-OH
of the inositol ring in the cell membrane (Toker and
Cantley, 1997). The best-known class of PI3Ks is a het-
erodimer composed of a regulatory subunit, p85, and
a catalytic subunit, p110. On activation by growth fac-
tor receptor protein tyrosine kinases, PI3K is recruited
to the cell membrane, where it phosphorylates PIPs to
generate the second messenger phosphatidylinositol-
3,4,5-triphosphate (PIP3). PIP3 then recruits a subset of
signaling proteins to the membrane, including protein
serine/threonine kinase 3'-phosphoinositide-depend-
ent kinase 1 (PDK1) and Akt/PKB. Akt is also a serine/
threonine kinase and is activated by phosphorylation
by PDK1 (Fresno Vara
et al.
, 2004). Activation of the
PI3K/Akt pathway induces cell growth and inhibits
apoptosis. As, Cd, Co, Ni, and V have been shown to
be able to activate the PI3K/Akt pathway.
B, and NFAT (Leon-
ard
et al.
, 2004a). Therefore, we have included ROS in
the discussion of the effects of metal compounds on
signaling pathways. Studies have shown that exposure
of cells to As, Cd, Co, Cr, Cu, Ni, as well as many other
metal compounds, can generate excessive ROS in cells
by Fenton-type reaction, Haber-Weiss reaction, or by
reacting directly with cellular molecules.
κ
6.2.4 HIF-1
6.2.2 MAPK
The transcription factor hypoxia-inducible factor 1
(HIF-1) plays an essential role in cellular oxygen home-
ostasis (Wang and Semenza, 1993). It is a heterodimer
composed of
The mitogen-activated protein kinase (MAPK) sig-
naling pathway plays an important role in controlling
gene expression programs in response to extracellular
signals in eukaryotic cells. There are four major groups
of MAPK family in mammalian cells, and they are ser-
ine/threonine kinases: extracellular signal regulated
kinase (ERK), c-jun N terminal kinase (JNK), p38, and
extracellular signal regulated kinase-5 (ERK5)/big
MAPK-1 (BMK1) (Lewis
et al.
, 1998). Each group also
contains a number of isoforms. MAPK signaling path-
ways feature a series of phosphorylation cascades. On
receiving extracellular signals such as growth factors,
hormones, and stress stimuli, the MAPKs are acti-
vated by phosphorylation on threonine and tyrosine
by the MAPK kinases (MAPKK), which are activated
α
- and
β
-subunits (Wang
et al.
, 1995). The
β
subunit, HIF-1
β
/ARNT, is constitutively expressed;
whereas the
) is highly oxygen sen-
sitive. It is rarely detectable under normal oxygen
tension but is dramatically induced in response to
hypoxia. Under reduced oxygen tension, HIF-1
α
subunit (HIF-1
α
is
stabilized and translocates to the nucleus, where it
dimerizes with HIF-1
α
and HIF-1 becomes activated
(Wang
et al.
, 1995). As a result, the activated HIF-1
stimulates the transcription of various cancer-related
genes involved in angiogenesis, cell survival, glucose
transport, and metabolism (Semenza, 2003). For exam-
ple, HIF-1 upregulates the vascular endothelial growth
β
