8.1 Introduction to Apoptosis

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What is Apoptosis?

 

Apoptosis is the process of active cell death resulting in the orderly breakdown of cellular structures (1). The term apoptosis is also commonly referred to as programmed cell death; an appropriate term since apoptosis is triggered by the expression of specific genes and blockage of mRNA or protein synthesis (2). In contrast, necrosis is the process of passive cell death resulting in cellular rupture and local inflammation (1). Apoptosis was not discovered until 1972, as cells are often phagocytosed before they are able to form apoptotic bodies (3).

 

Some of the major events of apoptosis include chromatin condensation and nuclear fragmentation (3). As the apoptosis proceeds, cell morphology becomes increasingly round and undergoes pyknosis (the reduction of cell volume) (3). Pseudopods are retracted and membrane blebbing occurs (3). Organelles undergo modifications as the cell begins to lose its membrane integrity (3). If dying cells are not phagocytosed (typically by macrophages), they undergo the process of secondary necrosis (3).

Figure 8.1.1. Necrosis (left) vs. Apoptosis (right) (By Zlir'a (Own work на основі зображення із статті) [Public domain], via Wikimedia Commons)

Three major biochemical events occur during apoptosis: activation of caspases, DNA and protein breakdown, and membrane modifications resulting in recognition by phagocytic cells (3). Apoptosis is an energy-dependent process. Early apoptosis is characterized by the breakdown of DNA into 50-300kb fragments (3). The DNA fragments are then cleaved into oligonucleotides by endonucleases (3). This results in a "ladder effect" of DNA fragments of a range of lengths that can be observed using agarose gel electrophoresis (3). Late apoptosis is characterized by the activation of cysteine proteases known as caspases (3). Caspases break down the protein and cytoskeletal components of the cell and activate DNase, which continues the degradation of the genome (3). There are two classes of caspases: initiators and effectors (3). A cascade of caspases breaks the cell into small membrane-covered vesicles by folding the cell inwards.  The cell membrane remains intact during the process despite vesicle budding. Phosphotidylserine, normally an intracellular transmembrane protein, is exposed on the surface and acts as a phagocytic signal to macrophages and dendritic cells to stimulate phagocytosis. These phagocytic cells also release cytokines which inhibit inflammation.

 

Here is a great video showing the signal cascade resulting in apoptosis of a cell: http://www.youtube.com/watch?v=9KTDz-ZisZ0

 

The process of apoptosis is divided into two pathways: the intrinsic mitochondrial pathway and the extrinsic death receptor pathway discussed in Section II. Apoptosis is regulated through a balance between pro-apoptotic and anti-apoptotic signals. An accumulation of pro-apoptotic signals result in apoptosis induction.  

 

Apoptosis plays a crucial role in both physiological and pathological conditions.

 

Apoptosis is an important part of normal cell homeostasis. It is implicated in both the cause and cure of many diseases, and understanding its role can allow for further insight on treatment. In cancer, the balance of survival and death signals is often dysregulated, as oncogenes and tumor suppressor genes often play a role in triggering apoptosis (3). The role of apoptosis in cancer will be further discussed in the later section, Apoptosis in Cancer

 

 


References:

1.     Cummings, M.C., Winterford, C.M., and Walker, N.I. (1997). Apoptosis. The American Journal of Surgical Pathology 21, 88–101.

2.     Cohen, J.J. (1993). Apoptosis. Immunology Today 14, 126–130.

3.     Wong, R.S.Y. (2011). Apoptosis in cancer: from pathogenesis to treatment. Journal of Experimental & Clinical Cancer Research : CR 30, 87.

4.     Scarabelli, T.M., Knight, R., Stephanou, A., Townsend, P., Chen-Scarabelli, C., Lawrence, K., Gottlieb, R., Latchman, D., and Narula, J. (2006). Clinical implications of apoptosis in ischemic myocardium. Current Problems in Cardiology 31, 181–264.

5.     Lowe, S.W., and Lin, A.W. (2000). Apoptosis in cancer. Carcinogenesis 21, 485–495.