Apoptosis is an important cellular process that allows cells to die in a programmed fashion. Apoptosis plays an essential role in growth and development, such as in the womb, where the fetal hand starts out as webbed, and fingers are formed through the programmed death of the cells in the web spaces. Apoptosis also plays an important role in removing faulty cells.
For example, pathological apoptosis may be induced if cellular DNA is damaged beyond repair. In apoptosis, the cell is broken down from within by proteins called caspases. For apoptosis to occur, these caspases first need to be activated.
Caspase activation can happen via two distinct pathways, called the extrinsic and intrinsic pathways. The first pathway is referred to as the extrinsic pathway because the initial signal comes from outside the cell. This pathway is often initiated by other cells, commonly by subsets of T lymphocytes.
These lymphocytes have a surface molecule known as FasLigand (or FasL for short). The extrinsic pathway is initiated when FasL binds to Fas receptors on the surface of the targeted cell. This sets off a chain of intracellular events that will ultimately result in apoptosis.
The sequence is mediated by a Fas Associated Death Domain or FADD. In the final step of the extrinsic pathway, caspases activate each other in a self-amplifying process called the ‘caspase cascade’. Apoptosis is then initiated as the active caspases begin the breakdown of cellular materials.
The caspase cascade acts as a common end-point for the second apoptotic pathway, known as the intrinsic pathway. As its name suggests, the intrinsic pathway is initiated by signals from within the cell. This intrinsic pathway is regulated by maintaining a balance between two sets of proteins in the mitochondrial membrane: anti-apoptotic proteins, such as Bcl-2 and Bcl-x, and pro-apoptotic proteins, such as Bax and Bak.
In a healthy cell, the anti-apoptotic proteins bind to the pro-apoptotic ones, thereby blocking their action. But if a cell is damaged or if it stops receiving survival signals, Bcl-2 and Bcl-x are blocked in turn. Bax and Bak are then free to punch a series of channels in mitochondria, allowing mitochondrial substances, such as cytochrome C, to leak out into the cytoplasm.
The leaked cytochrome C binds to Apaf-1 proteins to create a compound that then activates the caspase cascade. Apoptosis plays a key role in growth, immune surveillance and neoplastic development. In all of these processes, there can be abnormalities of too much or too little apoptosis.
For instance, cancer cells survive and replicate because they are able to block apoptosis. Understanding the functioning of the extrinsic and intrinsic pathways, as well as of the caspase cascade, allows us to design targeted therapies based on better regulation of apoptosis.
