Apoptotic Pathway – Our Cell is Going to Die

It has been long time I did not update the Cytogenetics and Cancer Research blog. Recently, I am celebrating the Chinese New Year. I am so happy to receive a lot of “Ang Pow” from the elders. Today, I will put on some information about the apoptotic pathway in this blog so that the readers can know how our cells die.

Apoptosis occurs in two signalling pathway which are extrinsic and intrinsic signalling pathway. The researchers try to look through the molecular pathways involved in the regulation of apoptosis in order to develop effective therapeutic approaches. There are many ways to induce apoptosis. One of it is to alter apoptosis threshold by modulating pro-apoptotic and anti-apoptotic members of Bcl-2 family.

apoptotic pathway,intrinsic extrinsic pathway,apoptosis

Figure 1: Apoptotic signalling pathways (Avi et. al., 2008).

Any stimuli that cause oxidative stress, mitochondrial disturbances and DNA damage may stimulate the intrinsic pathway. For example, cancer therapeutic agents, hypoxia, and ionizing irradiation can trigger intrinsic pathway of apoptosis. When the mitochondrial damage, the outer membrane will become permeable and facilitates cytochrome c release into cytoplasm. Then, the cytochrome c will bind to the caspase adaptor, Apaf-1 (apoptotic protease-activating factor-1), and consequently triggering the apoptotic cascade by activating procaspase 9. The apoptosome complex is formed. This complex will activate many downstream effector caspases like caspase 3, caspase 6 and caspase 7, leading to DNA fragmentation and cell death. Therefore, caspases play essential role in intrinsic apoptotic pathway. Meanwhile, the Bcl-2 family is another group of key players in intrinsic apoptotic pathway. The Bcl-2 family consists of more than 20 members of pro-apoptotic proteins and anti-apoptotic proteins. Members of the Bcl-2 family function as agonists or antagonists to each other as they can form homo- or heterodimers. Pro-apoptotic members of Bcl-2 family such as Bax, Bak, Bok, Bid and Bim can induce the release of cytochrome c from mitochondria. While anti-apoptotic members like Bcl-2, Bcl-XL and so on can bind to Apaf-1 to inactivate the intrinsic pathway. However, the pro-apoptotic members can dissociate the complex of anti-apoptotic members and Apaf-1 to allow the Apaf-1 to activate the caspase 9 and lead to subsequent apoptotic process. At the same time, Bax and Bak can promote apoptosis by triggering the release of Smac/DIABLO protein from mitochondria and subsequently inactivate the inhibitors of apoptosis proteins (IAP).

On the other hand, the extrinsic apoptotic pathway is induced by ligand binding of death receptors. The major ligand-death receptor system include tumor necrosis factor (TNF) with tumor necrosis factor receptor 1 (TNFR1), Fas ligand with Fas, and TRAIL with TRAIL receptors. The binding of the receptors with the ligands will induce the receptor oligomerization and recruitment of death signal adaptor proteins. These formed a complex termed DISC (death-inducing signalling complex), which can bind to initiator caspases like caspase 8 and caspase 10. Consequently, the caspase cascade will be triggered to activate the caspase 3, caspase 7 and caspase 9, and leading to apoptotic events.

In conclusion, there is an extensive crosstalk exists between the intrinsic and extrinsic apoptotic pathways. The activation of caspase cascade is the crucial component in the death process in either pathway. The pro-apoptotic and anti-apoptotic proteins can work together to maintain a dynamic balance between the survival and death of the cell.

Apoptotic Pathway – Our Cell is Going to Die is a post from: Cytogenetics and Cancer Research