In this article we will discuss about:- 1. Introduction to Apoptosis 2. Cellular Events of Apoptosis 3. Mechanism 4. Importance.
Introduction to Apoptosis:
Every normal living cell of animals, plants and even bacteria are mortal. I.e., they must die after some time. Cell death is a finely tuned programme inherent in the cells genetic machinery. This normal cell death which is the part of normal development and maintenance of homeostasis is called apoptosis or programmed cell death (PCD).
This phenomenon is very much different from death of a cell due to pathological cause or necrosis. This process is highly regulated and any defect in apoptotic machinery will lead to extended survival of cells which may result in neoplastic cell expansion, leading to genetic instability and accumulation of mutations.
Cellular Events of Apoptosis:
It is a normal physiological response to specific suicide signals or lack of survival signals. During this process at first the nucleus and cytoplasm condense, i.e., chromatin material condenses and migrates to nuclear membrane, the cytoplasm undergoes shrinkage without any damage to plasma membrane.
The cell contents are packaged in membrane bound bodies and the cell is broken down into pieces called apoptotic pieces, though still functioning, are engulfed or phagocytosed or digested by macrophages or by neighbouring cells (Fig. 5.33).
Mechanism of Apoptosis:
There are three major pathways for activation of caspase which causes cleavage of substrates leading to apoptosis.
i. Mitochondrial/Cytochrome pathway:
It is mediated through activation of Bcl-2 (gene) which results in production of Apaf-1, caspase-9 and caspase-3 enzyme synthesis which leads to the phenomenon of apoptosis (Fig. 5.34).
ii. Tumour-necrosis factor-receptor (TNF) pathway:
In this pathway the ligation of members of the TNF-receptors takes place, activating caspase-8 and then caspase-3 which leads to apoptosis.
iii. Granazyme B pathway:
Granazyme B, a cytosolic T cell product, directly cleaves and activates several caspases, resulting in apoptosis. A number of genes have been identified which play role in the regulation and accomplishment of apoptosis, such as egl-1, Ced-1-10. Studies on these genes indicated that Ced-9 acts upstream of Ced-3 and Ced-4 (Fig. 5.35):
Ced-9 → Ced-3→Ced-4→Cell death
Ced-3 and Ced-4 promote apoptosis, while Ced-9 Is anti-apoptotic and protects cells from apoptosis by antagonizing Ced-3 and Ced-4. The Ced genes are responsible for all programmed cell death.
Caspases are cysteine proteases which cleave the substrates at the C-terminal of an aspartic acid residue. Different caspases have different substrate recognition preferences and cleavage of substrates by caspases results in disassembly and consequent death of cell in a highly organized manner.
Death receptors are important in ‘instructive’ apoptosis where ceil death is brought about by the secretion of death legends which bind to death receptors on the target cell (Fig. 5.36).
Importance of Apoptosis:
It is a necessary mechanism complementary to proliferation to ensure homeostasis in all tissues. Removal of a number of vestigeal structures (developmental structure, e.g., tail) is caused by programmed cell death. Apoptosis is considered a necessary anticancer mechanism, as defect in this process leads to neoplastic and tumorigenic cell development.