Biomedical Engineering Reference
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(Bax, Bak and Bok) and “BH3-domain only” members (Bim,
Bad, Bid, Bik, Bmf, Puma, Noxa and Hrk). Pro- and anti-apoptotic
family members may heterodimerize, thereby affecting their
respective functions, and their activity is regulated either at the
transcriptional or posttranslational levels.
Bad (Bcl-2 antagonist of cell death) is a positive regulator of
cell death and, like other BH3-only proteins, selectively displaces
Bax to heterodimerize with Bcl-2 or BclX
L
. Thus, Bad may acti-
vate Bax simply by freeing it from the above pro-survival proteins.
The pro-death effect of Bad is dependent on its ability to dimerise
with pro-survival members of the Bcl-2 family (
1, 2
).
In the absence of survival stimuli, endogenous Bad is dephos-
phorylated and localized in the outer mitochondrial membrane.
In the presence of survival factors, Bad is promptly phosphory-
lated on serine 136 by phosphatidylinositol 3-kinase/Akt (
3, 4
)
or on serine 112 by either protein kinase A (PKA) or protein
kinase C (PKC)/p90
RSK
(
5, 6
). Phosphorylation at serine 112, or
136, allows Bad sequestration in the cytoplasm, bound to 14-3-3
scaffold proteins. PKA-dependent phosphorylation at serine 155
has also been reported and shown to reduce the affinity of Bad for
pro-survival Bcl-2 family members (
7
).
Our previous work has shown that pro-monocytic cell lines,
and human monocytes/macrophages, survive to peroxynitrite
because of their ability to respond to molecules largely available
in the inflammatory milieu (e.g. arachidonic acid) with the trig-
gering of events converging in Bad phosphorylation (
8, 9
).
In particular, we showed that 5-hydroxyeicosatetraenoic acid
(5-HETE), a product of 5-lipoxygenase (5-LO), promotes the
mitochondrial translocation of PKCa and the ensuing phospho-
rylation of Bad (
10
). Inhibition of the survival signaling at the
level of cytosolic phospholipase A
2
, 5-LO or PKCa rapidly leads
to the mitochondrial accumulation of Bad, associated with the
rapid onset of mitochondrial permeability transition (MPT)-
dependent toxicity. Cells, however, can nevertheless be rescued
by supplementation of products downstream to the inhibited
step or, in alternative, via EP
2
receptor-mediated, PKA-
dependent Bad phosphorylation elicited by exogenous PGE
2
(
11
). A third Bad kinase, Akt, is severely inhibited by peroxyni-
trite in U937 cells.
In short, the survival strategy adopted by monocytes/mac-
rophages to cope with peroxynitrite is simple, yet very effective:
while committed to MPT-dependent toxicity, these cells never-
theless survive by promoting Bad phosphorylation via different
pathways. It is interesting to note that these pathways are triggered
by molecules extensively produced under inflammatory condi-
tions (as peroxynitrite) by monocytes/macrophages themselves,
as well as by other cell types.
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