41. Apoptosis: definition, activation pathways, activator genes, receptors, role of caspases. Variants of apoptosis regulation disorders, role in pathology, examples of pathological processes.

The process of apoptosis can be divided into 2 (two) phases:

1. The formation and conduct of apoptic signals is the decision–making phase.

2. Dismantling of cellular structures is an effector phase.

1. The 1st phase is decision-making (=formation and acceptance of apoptic signals). This is the phase of accepting stimuli for apoptosis. Depending on the nature of the stimuli, there may be 2 (two) types of signaling pathways

1. DNA damage as a result of radiation, toxic agents, glucocorticoids, etc.

2. activation of the receptors of the "cell death region". The receptors of the "cell death region" are a group of receptors on the membranes of any cells that perceive pro-apoptic stimuli. If the number and activity of such receptors increases, then the number of apoptically dying cells increases. The receptors of the "cell death region" include: a) TNF-R (binds to tumor necrosis factor and activates apoptosis); b) Fas-R (k); c) CD45-R (binds to antibodies and activates apoptosis).

Depending on the type of signal, there are 2 (two) main ways of apoptosis:

1. as a result of DNA damage;

2. as a result of self-activation of the receptors of the "cell death region" without DNA damage.

1. The 2nd phase is effector - dismantling of cellular structures. The main figures of the effector phase:

1. cysteine proteases (caspases);

2. endonucleases;

3. serine and lysosomal proteases;

4. proteases activated by Ca++ (calpain)

5. Among them, the main effectors of dismantling cellular structures are caspases.

The main inductors are caspases 8 and 9. They activate effector caspases. The mechanism is the cleavage of aspartic bases followed by dimerization of active subunits. These caspases are inactive in their normal state in cells, they exist in the form of procaspases.

The activation of certain inductors depends on the type of signaling pathway:

1. When DNA is damaged, signaling pathway No. 1 is involved, and caspase No. 9 is activated.

2. When cell death receptors are activated, signaling pathway No. 2 is involved, and caspase No. 8 is activated.

Signaling pathway No. 1 (associated with DNA damage)

DNA damage

↓

Activation of the p53 gene and production of the corresponding protein

↓

Activation of pro-apoptic genes of the BCL-2 family (BAX and BID)

↓

The formation of proteins of these genes

↓

Activation of caspase 9

↓

Activation of caspase 3

+↓

Activation of other caspases and proteases

↓

Apoptosis

Signaling pathway No. 2 (associated with activation of the "cell death region")

Ligand + receptors of the "cell death region"

↓

Activation of caspase No. 8

↓

Independent activation of caspase No. 3

+↓

Activation of other caspases and proteases

↓

Apoptosis

The main task of regulating apoptosis is to keep effector caspases inactive, but quickly convert them into an active form in response to the minimal action of the corresponding inducers.

Hence, the concept of inhibitors and activators of apoptosis.Inhibitors of apoptosis (anti-apoptotic factors). The most serious inhibitors of apoptosis include growth factors. Others: neutral amino acids, zinc, estrogens, androgens, some proteins. Activators of apoptosis (pro-apoptic factors). These are pro-apoptic genes and their products: a) BCL-2 family genes (BAX and BID); b) Rb and P53 genes (trigger apoptosis if the cell is delayed by the checkpoint mechanism.