Calcium Biochemistry
143
PCD is an important mechanism during
development that has emerged in multicel-
lular organisms to remove unnecessary,
damaged, or aged cells. Therefore, ab-
normal resistance toward apoptosis may
lead to autoimmune diseases or can-
cer, whereas uncontrolled enhancement
of apoptotic processes could favor chronic
pathologies such as neurodegenerative dis-
eases (e.g. dementia of the Alzheimer type)
or immune deFciencies such as AIDS.
A number of highly conserved pro-
teins, called
death proteins
,a
r
ein
v
o
l
v
ed
in the complex apoptotic pathways by ei-
ther causing or preventing cell death. This
was mainly due to detailed studies of the
nematode
Caenorhabditis elegans
.Du
r
ing
development, 131 of the total 1090 cells
of
C. elegans
are predestined to die. This
apoptotic process is controlled by the co-
ordinated expression of the death proteins
ced-3, ced-4, and ced-9, some of which
belong to the highly conserved family of
cysteine proteases, called
caspases
,o
the
rs
to oncogenes such as bcl-2.
Work in a number of different labs
has demonstrated that alterations in intra-
cellular Ca
2
+
homeostasis are commonly
involved in promoting apoptosis. One as-
pect of the function of bcl-2 involves
preventing these alterations. So it has been
demonstrated that sustained levels of Ca
2
+
in mitochondria can be signiFcantly low-
ered by the expression of bcl-2 and that
bcl-2 can block the depletion of endoplas-
mic reticular Ca
2
+
stores. In addition, it
has been shown that IP
3
-dependent Ca
2
+
release is essential for triggering apoptosis.
One of the consequences may lead to the
activation of Ca
2
+
-dependent endonucle-
ases that are responsible for the cleavage of
DNA linker regions between nucleosomes,
leading to the frequently observed DNA
laddering during apoptotic processes.
Another interesting link between Ca
2
+
and apoptosis was recently reported by
the discovery of a new member of a Ca
2
+
binding protein of the E±-hand type, called
ALG-2, which was linked to apoptosis
(see below). It was observed that T-cell
hybridomas depleted of ALG-2 were pro-
tected against PCD induced by a variety
of stimuli including dexamethasone and
±as/CD95 triggering. Evidence was pro-
vided that members of the ICE protease
family were activated upon stimulation
by either ±as/APO-1 antibodies or dex-
amethasone in ALG-2 depleted cells, but
progression of cell death was impaired
indicating that ALG-2 is necessary for the
apoptotic function of ICE/Ced-3 proteases.
However, later it was reported that mice
lacking the
ALG-2
gene not only developed
normally but it was also observed that in T
cells obtained from those mice, apoptotic
processes could be induced indicating that
ALG-2 is not essential for apoptosis.
By using a similar functional selection
strategy of cloning to identify genes linked
to PCD, a
d
eath
a
ssociated
p
rotein (DAP)
was identiFed as a kinase, therefore called
DAP-kinase. This protein turned out to
be a Ca
2
+
-calmodulin-dependent kinase of
160 kDa. It is speciFc for phosphorylating
serine/threonine residues, and contains a
number of other domains such as ankyrin
repeats, P-loops, cytoskeleton binding do-
mains, and death domains. It was demon-
strated that the enzyme phosphorylated
myosin light chains in a Ca
2
+
-calmodulin-
dependent manner and is associated with
the cytoskeleton of the cells. The latter
observation could be of special interest
since changes in the actin microFlament of
the cytoskeleton organization preceded the
nuclear condensation and segmentation
in response to interferon-
γ
-stimulation or
DAP-kinase overexpression.
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