Apoptosis
Why should a cell commit suicide?
There are two different reasons.
1. Programmed cell death is as needed for proper development as mitosis
is.
Examples:
- The resorption
of the tadpole tail at the time of its metamorphosis into a frog occurs by
apoptosis.
- The
formation of the fingers and toes of the fetus requires the removal, by apoptosis,
of the tissue between them.
- The sloughing off of the
inner lining of the uterus (the endometrium) at
the start of menstruation occurs by apoptosis.
- The formation of the
proper connections (synapses) between neurons in the brain requires
that surplus cells be eliminated by apoptosis
2. Programmed cell death is needed to destroy cells that
represent a threat to the integrity of the organism.
Examples:
Cells infected with viruses
One of
the methods by which cytotoxic T lymphocytes (CTLs)
kill virus-infected cells is by inducing apoptosis [diagram of the mechanism]. (And some viruses
mount countermeasures to thwart it — Link)
Cells of the immune system
As cell-mediated immune responses wane, the effector cells must be removed to prevent them from
attacking body constituents. CTLs induce apoptosis in
each other and even in themselves. Defects in the apoptotic
machinery is associated with autoimmune diseases such as lupus erythematosus
and rheumatoid arthritis.
Cells with DNA damage
Damage to
its genome can cause a cell
·
to disrupt proper
embryonic development leading to birth defects
·
to become cancerous.
Cells
respond to DNA damage by increasing their production of p53. p53 is a potent inducer
of apoptosis. Is it any wonder that mutations in the p53 gene, producing
a defective protein, are so often found in cancer cells (that represent a
lethal threat to the organism if permitted to live)?
Cancer cells
Radiation and chemicals used in
cancer therapy induce apoptosis in some types of cancer cells.
What makes a cell decide to commit suicide?
The balance between:
- the withdrawal of positive
signals; that is, signals needed for continued survival, and
- the
receipt of negative signals.
Withdrawal
of positive signals
The continued survival of most cells requires that they
receive continuous stimulation from other cells and, for many, continued
adhesion to the surface on which they are growing. Some examples of positive
signals:
- growth
factors for neurons
- Interleukin-2 (IL-2), an essential factor for the
mitosis of lymphocytes
Receipt of negative
signals
- increased levels of
oxidants within the cell
- damage to DNA by these
oxidants or other agents like
- accumulation of proteins
that failed to fold properly into their proper tertiary structure
- molecules
that bind to specific receptors on the cell surface and signal the cell to
begin the apoptosis program. These death activators include:
- Tumor necrosis
factor-alpha (TNF-α ) that binds to the TNF receptor;
- Lymphotoxin
(also known as TNF-β ) that also binds to the TNF receptor;
- Fas
ligand (FasL),
a molecule that binds to a cell-surface receptor named Fas (also called CD95).
The
Mechanisms of Apoptosis
There are 3 different mechanisms by which a cell commits
suicide by apoptosis.
- One generated by signals
arising within the cell;
- another triggered by death activators
binding to receptors at the cell surface:
- TNF-α
- Lymphotoxin
- Fas
ligand (FasL)
- A third that may be triggered by dangerous reactive oxygen species.
1. Apoptosis triggered by internal signals: the intrinsic or
mitochondrial pathway
In a healthy cell, the outer membranes of
its mitochondria express the protein Bcl-2 on their surface. - Bcl-2 is bound to a
molecule of the protein Apaf-1 ("apoptotic protease activating
factor-1".
- Internal damage
to the cell (e.g., from reactive oxygen species) causes
- Bcl-2 to release
Apaf-1;
- a related protein, Bax, to penetrate mitochondrial membranes,
causing
- cytochrome c to leak out.
- The released cytochrome c and Apaf-1 bind to molecules of caspase 9.
- The resulting complex of
- cytochrome
c
- Apaf-1
- caspase
9
- (and ATP)
is called the apoptosome.
- These aggregate in the cytosol.
- Caspase
9 is one of a family of over a dozen caspases.
They are all proteases. They get their name because they
cleave proteins — mostly each other — at aspartic acid (Asp) residues).
- Caspase
9 cleaves and, in so doing, activates other caspases.
- The sequential
activation of one caspase by another creates an
expanding cascade of proteolytic activity
(rather like that in blood clotting and complement activation) which leads to
- digestion of
structural proteins in the cytoplasm,
- degradation of
chromosomal DNA, and
- phagocytosis of the cell.
2. Apoptosis triggered by external signals: the extrinsic
or death receptor pathway
Fas and the TNF receptor are integral membrane proteins with their
receptor domains exposed at the surface of the cell - binding of the complementary death
activator (FasL and TNF
respectively) transmits a signal to the cytoplasm that leads to
- activation of caspase 8
- caspase
8 (like caspase 9) initiates a cascade of caspase activation leading to
- phagocytosis of the cell.
Example (right): When cytotoxic T cells recognize (bind to) their target,
- they
produce more FasL at their surface.
- This binds with the Fas on the surface of the target cell leading
to its death by apoptosis.
The early steps in apoptosis are reversible — at
least in C. elegans. In some
cases, final destruction of the cell is guaranteed only with its engulfment by
a phagocyte.
3.
Apoptosis-Inducing Factor (AIF)
Neurons, and perhaps other cells, have another way
to self-destruct that — unlike the two paths described above — does not use caspases.
Apoptosis-inducing factor (AIF)
is a protein that is normally located in the intermembrane space of mitochondria. When the cell receives a
signal telling it that it is time to die, AIF
- is released from the
mitochondria (like the release of cytochrome c
in the first pathway);
- migrates into the
nucleus;
- binds to DNA, which
- triggers
the destruction of the DNA and cell death.