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).
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,
Figure 4.1: Intrinsic
pathway of apoptosis (Amaral, 2008).
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).
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).
Figure 4.2: 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).
Figure 4.3: Regulation
mechanism of p53 gene (Phillipyau, 2004).
P53 regulates the expression of p21, GADD45 or
14-3-3 inhibitory proteins to mediate growth arrest. In apoptosis, p53
activates the expression of Apaf-1 and BAX which stimulates the release of cytochrome
C in intrinsic pathway (Fulda and Debatin, 2006).