Molecular Biology Tutorials

Extrinsic Pathway of Apoptosis (Apoptosis Molecular Mechanism Part 2)


Receptor Mediated Apoptosis

Extrinsic Pathway of Apoptosis
(The Receptor-Mediated Programmed Cell Death Pathway)

In the extrinsic pathway of apoptosis, the death-inducing signal for the programmed cell death is triggered by an external stimulus. For receiving such an external death-inducing signal, the cell possesses plasma membrane receptors specific to each stimulus and thus the extrinsic signalling of apoptosis is also known as the Receptor Mediated programmed cell death pathway.

The external stimuli for the apoptosis in most of the cases will be a cytokine. The most studied cytokine to induce extrinsic pathway of apoptosis is an extracellular messenger protein called Tumor Necrosis Factor (TNF). TNF is so named because it was first discovered as a protein factor which induces cell death in cancerous cells. The TNF cytokine is produced by the cells of the immune system in response towards the adverse conditions. The adverse conditions that can provoke the immune cells to produce TNF are:

Ø  Exposure to radiation

Ø  Introduction of viral toxins

Ø  Exposure to elevated temperature

Ø  Exposure to other toxic substances

The detailed signaling mechanism of TNF-mediated extrinsic pathway of apoptosis is summarized below:

Ø  TNF first binds to its receptor called TNFR1 (Tumor Necrosis Factor Receptor-1) present on the plasma membrane.

Ø  TNFR1 is a member of death receptor family proteins that turn on the apoptotic cell death process in eukaryotic cells.

Ø  TNFR1 is a trans-membrane receptor with an external ligand binding domain and a cytosolic domain.

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Molecular Biology Tutorials

Intrinsic Pathway of Apoptosis (Apoptosis Molecular Mechanism Part 1)


Mitochondrial Apoptosis Signaling

Intrinsic Pathway of Apoptosis
(The Mitochondria Mediated Programmed Cell Death Pathway)

In the previous post, we have discussed the characteristic features and significance of programmed cell death or apoptosis. As we discussed, the stimuli for the execution of programmed cell death can be of internal or external to the apoptotic cell. Based on the source of stimuli, there are two types of apoptosis signaling pathways operate in the cells. They are (1) Intrinsic pathway (stimuli are internal) and (2) Extrinsic pathway (stimuli are external) of apoptosis. Even though both the intrinsic and extrinsic pathways considerably different, there is always cross-talk between these two pathways. In the present post, we will discuss the details of INTRINSIC PATHWAY of apoptosis signalling.

What is meant by Intrinsic Pathway of Apoptosis?

In the intrinsic pathway of apoptosis, the death-inducing stimuli are originated inside the target cell itself. Mitochondria, the powerhouse of the cell, have a significant role in executing the intrinsic pathway of apoptosis. Thus, the intrinsic pathway of apoptosis is also known as the Mitochondria-mediated death pathway.

What are the stimuli for the intrinsic pathway of apoptosis?

Most commonly observed internal stimuli for the initiation of the intrinsic pathway of apoptosis are:

Ø  Severe genetic damage

Ø  Lack of oxygen (hypoxia)

Ø  Very high concentration of cytosolic Ca2+ ions

Ø  Presence of some viral proteins

Ø  Severe oxidative stress due to the production of free radicals

What are Bcl-2 (B-cell lymphoma-2) family proteins?

The intrinsic pathway of apoptosis is facilitated by the members of Bcl-2 family proteins. The members of the Bcl-2 family proteins are characterized by the presence of one or more BH domains (Bcl-2 Homology Domain). The first identified member of Bcl-2 family proteins is Bcl-2 itself. The Bcl-2 was first identified as a cancer-causing oncogene in some human lymphomas. The gene which codes for the Bcl-2 protein was over-expressed in these cancer cells due to translocation. However, later studies have shown that Bcl-2 is not directly acting as an oncogene. They act as the oncogene by promoting the survival of the cancerous cells that would otherwise die by apoptosis.

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