Apoptosis

Introduction to Apoptosis

Apoptosis refers to the set of ordered biochemical and physical changes in a cell during a specific form of cell death. These changes begin with the rounding and shrinking of the affected cells causing them to lose contact with their neighbors. Later, their endoplasmic reticulum swells and the cisternae begin to form vesicles and vacuoles. In the nucleus, the chromatin condenses and is digested by endogenous nucleases. The nucleus ultimately disintegrates into fragments which are encapsulated into "apoptotic bodies". By this point, the plasma membrane has become convoluted and begins blebbing off, forming the surface of the apoptotic bodies, which are then recognized and engulfed by phagocytic cells. In contrast, during necrosis the cell swells and disintegrates in a disordered manner, leading to the destruction of cellular organelles and the rupture of the plasma membrane.

The term apoptosis was first introduced in 1972 (Kerr et al., 1972) and since then there have been over 80,000 papers published on the subject. It is known to play a role in multiple diseases, such as degenerative diseases (Alzheimer's, spinal muscular dystrophy, AIDS) where there is too much apoptosis, and various forms of cancers, where there is too little apoptosis. Furthermore, it has been recognized to also be important in the development of an organism.

The basic apoptotic pathway and proteins have been highly conserved throughout evolution. In C. elegans, only 3 genes (ced-3, ced-4, and ced-9) are needed to comprise the programmed cell death machinery for the 131 cells that undergo apoptosis during development (reviewed in Metzstein et al., 1998). As organisms became more complex, other proteins evolved to assume several of the functions of the CED proteins. In mammalian cells, the functions of these 3 ced proteins are assumed by the Bcl-2 family of proteins, Apaf-1 and related proteins, and the several members of the caspase protease family.

Apoptosis can be separated into 2 classes: the intrinsic pathway, including programmed cell death, and the extrinsic pathway, in which receptor-mediated apoptosis is triggered by extracellular ligands or even the removal of growth factors. In this pathway, apoptosis is induced by the binding of extracellular ligands to receptors such as Fas (also termed Apo1 or CD95) and the tumor necrosis factor receptor (TNF-R). As with several other apoptosis-inducing receptors, these molecules have a cytosolic "death domain" that binds adaptor proteins that ultimately activate various caspases leading to cell death (reviewed in Bhardwaj and Aggarwal, 2003).

Caspases (Cysteine ASPartic acid proteASES) that are involved in cell death cleave cellular substrates on activation causing the general morphological features associated with apoptosis (reviewed in Salvesen and Abrams, 2004). These substrates include actin, fodrin, and lamin, as well as ICAD (inhibitor of caspase-activated DNase), which allows the activation of CAD (caspase-activated DNase) and its migration into the nucleus, thereby facillitating DNA cleavage and ultimately cell death.

The intrinsic pathway of apoptosis converges with the extrinisic pathway at the level of caspase activation. Instead of external signals transduced across the cell membrane by receptors however, the triggering signals are usually extra- or intracellular stresses. A major area of study is the effect of oxidative stress on the induction of apoptosis. Damage caused by reactive oxygen species appears to disrupt mitochrondial membrane potential and allow the leakage of cytochrome c from the mitochondiral intermembrane space into the cytoplasm. This permits the binding of cytochrome c by Apaf-1 and the formation of the apoptosome, a large oligomeric complex containing 7 each of Apaf-1, cytochrome c, ATP, and procaspase-9. This complex, termed the apoptosome, catalyzes the activation of other caspases, leading to cell death (Waterhouse et al., 2002).

While much is now known about the regulation and mechanisms of apoptosis, there are still aspects of this process that remain poorly understood. By identifying the molecular components and mechanisms of apoptosis, treatments may be developed to modulate the apoptotic processes in diseases such as cancer and degenerative disorders.

References

1. Bhardwaj A and Aggarwal BB. (2003) Receptor-mediated choreography of life and death. J. Clin. Immunol. 23:317-332.
2. Kerr JF, Wyllie AH, and Currie AR. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26:239-257.
3. Metzstein MM, Stanfield GM, Horvitz HR. (1998) Genetics of programmed cell death in C. elegans: past, present, and future. Trends Genet. 14:410-416.
4. Salvesen GS and Abrams JM. (2004) Caspase activation – stepping on the gas or releasing the brakes? Lessons from humans and flies. Oncogene 23:2774-2784.
5. Waterhouse NJ, Ricci JE, and Green DR. (2002) And all of a sudden it's over: mitochondrial outer-membrane permeabilization in apoptosis. Biochimie 84:113-121.