Apoptosis is a common programmed cell death which eliminates cells that are not required, dislocated or badly damaged in our body (Amaral, 2008). This process can trigger by two major pathways which are either intrinsic pathway or extrinsic pathway (Phillipyau, 2004).
Cellular stress or mitochondrial stress caused by DNA damage, radiation, nutrient deficiency, viral infection and heat stock triggers the intrinsic pathway (Kabel et al, 2016). When a stress signal enters, the proapoptotic proteins in the cytoplasm (BAX and BID) bind to the outer membrane of the mitochondria and release signal of the internal content (Fulda and Debatin, 2006). The signal of BAX and BID is not enough to generate the reaction (Phillipyau, 2004). BAK is another proapoptotic protein that needed to promote the complete release of cytochrome C and the intramembrane content from the mitochondria (Fulda and Debatin, 2006). Cytochrome C forms a complex in the cytoplasm with adenosine triphosphate (ATP) and Apaf-1 enzyme. This complex activates an initiator protein called as caspase-9 (Amaral, 2008).
Intrinsic pathway of apoptosis (Amaral, 2008). Activated caspase-9 reacts with the cytochrome C complex, ATP and Apaf-1 to form an apoptosome. It will activate the effector protein known as caspase-3 that initiates degradation (Phillipyau, 2004). The release of cytochrome C from the intramembrane space, the intramembrane content released also contains apoptosis inducing factor (AIF) to facilitate DNA fragmentation, and Smac/Diablo proteins to inhibit the inhibitor of apoptosis (IAP) (Fulda and Debatin, 2006).
In the extrinsic pathway, ligands (signal molecules) bind to transmembrane death receptors on the target cell to stimulate apoptosis (Kabel et al, 2016). Cells possess the Fas ligand (FasL) on their surface (Fulda and Debatin, 2006). FasL binds with the Fas receptors (a death receptor) on the target cell and triggers the aggregation of multiple receptors together on the surface of the target cell. To aggregate these receptors recruits an adaptor protein known as Fas-associated death domain protein (FADD) on the cytoplasmic side of the receptors (Phillipyau, 2004). FADD recruits an initiator protein known as caspase-8 to form the death-inducing signal complex (DISC). The recruitment of caspase-8 to DISC, caspase-8 will be activated and it directly activates an effector protein known as caspase-3 to initiate degradation of the cell. Activated caspase-8 converts BID protein to tBID, which acts as a signal on the membrane of mitochondria to initiate the release of cytochrome C in the intrinsic pathway (Fulda and Debatin, 2006).
Extrinsic pathway of apoptosis (Amaral, 2008). P53 protein is a specific DNA-binding protein that induces either cell cycle arrest or apoptosis in damaged or transformed cells (Kabel et al, 2016). It plays a major role in the DNA damage induced ultraviolet (UV) radiation, toxins and hormones (Fulda and Debatin, 2006).
The p53 gene regulates apoptosis by some important regulation mechanisms. Mdm2 is the main regulator of p53 gene. Initially p53 activates the expression of Mdm2. The p53 gene degrades by binding with the Mdm2 in ubiquitin system. In normal cells phosphorylation of p53 prevents the binding of Mdm2 gene to avoid degradation. Damaged DNA activates protein kinase (ATM, DNA-PK) to phosporylate p53. It increases the p53 level which in trn increases Mdm2 release and initiates apoptosis (Phillipyau, 2004).