Genetics of Apoptosis
Apoptosis only occurs when the cell activates a series of proteases called caspases,
which are responsible for cleaving proteins inside the cell.
Caspases stand for Cysteine Aspartate Specific ProteASEs, and they act by
cleaving protein substrates along their amino acid sequences after an aspartic acid
residue. By cleaving proteins, caspases
essential cut the internal structures of the cell to pieces, cause the cytoskeleton
to collapse and the cytoplasm to shrink.
Specific proteins, and thus the genes that code for them, are responsible for activating
or inhibiting the action of these caspases.
Therefore, there is a constant, intricate play between activation and inhibition
of these caspases and ultimately controls the fate of each and every cell.
Basically stated, caspases involved in apoptosis are activated by Apaf-1,
Fas, and Bax proteins and inhibited by Bcl-2 protein.
Pathway 1: Mitochondrial Membrane and Cytochrome c
In normal, healthy cells, the mitochondrial outer membrane displays the Bcl-2 protein
on its outer surface. The presence
of this protein depends on the transcription and translation of the Bcl-2 gene,
and therefore the inhibition of apoptosis.
When damage occurs to the cell, resulting in DNA damage or organelle damage that
cannot be fixed, Bcl-2 activates the expression of the Bax gene, which produces
the Bas protein. The Bax protein inhibits
the action of the Bcl-2 protein. Therefore
the Bax protein inhibits the inhibitor of apoptosis, meaning that it essentially
helps to activate the apoptotic pathway.
Bax works by basically “punching holes” in the outer mitochondrial membrane, which
allows cytochrome c to leak out into the cytoplasm where it binds with the Apaf-1
protein. Apaf-1 stands for apoptotic
protease activating factor-1. Using
ATP to help catalyze the reaction between Apaf-1 and cytochrome c, an apoptosome
is formed. This apoptosome is able
to bind and activate caspase-9. Thus,
the apoptotic caspases are activated.
Caspase-9 is only one of about a dozen caspases in mammalian cells and activation
of these caspases causes the overall increase in proteolytic activity resulting
in structural protein (cytoskeleton) and chromatin (chromosomal DNA) digestion. Eventually the cell is phagocytised
by incoming macrophages, which are responsible for cleaning up tissues of debris.
Pathway 2: External Signals – the Death Receptor Pathway
Two integral membrane proteins found on the outside of the cell membrane are the
Fas and TNF receptors. When these receptors
are triggered by extracellular signals, they activate caspase 8 and thus begin the
apoptotic pathway. These extracellular
signals are FasL, which stimulates the Fas receptor, and TNF, which stimulates the
TNF receptor. Thus, these extracellular
signals are called death activators.
The signal transmission stimulates the activation of caspase 8 and the corresponding
cascade of caspase activation causing the eventually phagocytosis of the cell.
Where do the death activators originate?
Cytotoxic T cells, or killer T cells of the immune system, express FasL on their
cell surfaces and bind with the Fas receptors of damaged or targeted cells. Therefore, if a particular cell has
been infected or targeted for destruction, the apoptotic pathway can be stimulated
via the cytotoxic T cell pathway.
Pathway 3: Non-caspase Self-destruction using AIF
AIF is apoptosis inducing factor and it is found in neurons, cells that do not contain
caspases and therefore cannot utilize the two pathways above.
This protein is located in the intermembrane space of the neuron’s mitochondria. When this protein is released from the
inter-mitochondrial membrane, which occurs when the neuron receives an apoptotic
signal, it migrates to the nucleus where it binds to DNA, triggers DNA destruction,
and causes cell death.
This brief summary of the genetics of apoptosis does not cover the entire catalog of apoptosis genes related to the process. For a more in depth review of each gene and the role that their proteins play in this pathway, please visit: http://www.biosource.com/content/apop/glossary.html
References
“Apoptosis”. Reproductive and Cardiovascular Disease Research Group.(online). Retrieved April 25, 2006 from: http://www.sgul.ac.uk/depts/immunology/~dash/apoptosis/
“Apoptosis” Oct 2005. Retrieved from: http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html#CTL
“Caspase 7” Retrieved from: http://www.caspases.org/
Image Gallery, Clinical Tools (online). Retrieved from: http://www1.geneticsolutions.com/PageReq?id=3844:1873
“Apoptosis Glossary Version 1.3” Retrieved from: http://www.biosource.com/content/apop/glossary.html
“Apoptosis” Neuromuscular (online). Retrieved from: http://www.neuro.wustl.edu/neuromuscular/mother/apoptosis.htm