13. Programmed cell death (pcd)

The term “apoptosis” means from Greek “removal, separating”. Galen and Hippocrate designated “apoptosis” annual essential leaves fall. “Apo”- “complete”, “ptosis” – “falling down, loosing”. In 1972 Kerr, Willie and Curi have proposed to use the term “apoptosis” for cellular death special designation different from necrosis.

Many scientists put sign of equality between programmed cell death and apoptosis. But these terms have differencies.

1. PCD is embryogenesis characteristics mainly of embryonal neurons and cells of connective tissue, apoptosis – for postembryonic development (thymocytes, lymphocytes after glucocorticoids action, prostate after castration, atrophy et al.).

2. Main square for evnts at PCD is cytoplasma (changing of pattern-synthesizing proteins), apoptosis – nucleus (endonuclease activation). Proteins changing and endonuclease activation are primary manifestations of 2 cellular death types.

3 Main biochemical changings in nucleus: at apoptosis occur DNA internucleosomal degradation (ruptures); it is absent at PCD.

4. Biochemical changings in cytoplasm at PCD – lysosomal enzymes amount increasing, sometimes – synthesis of heat shock proteins; at apoptosis – lysosomal enzymes amount is not increased, sometimes – specific proteins synthesis.

5. Apoptic bodies phagocytosis at PCD lasts for several hours, at apoptosis – from several minutes from 1 hour.

3 Apoptosis phases:

1. Inductory – apoptosis triggering by signals accept; it is expressed differently dependently on cells types and triggering factors.

2. Effector – similar for all apoptosis types.

3. Degradation - similar for all apoptosis types.

Reasons:

I. 1. Specific stimuli action such as TNF, FAS, IL-1, 10, TGF-beta, INF-gamma, cytokines.

2. Radiations (low dosages).

3. Cytostatics.

4. Glucocorticoids.

5.Angiotensine.

6. ATP.

7. Morphine.

8. Temperature increasing.

9. Viruses.

10. Toxic agents.

They act at first stage.

II. Intracellular inducing agents:

1. Heat shock proteins.

2. p53.

3. Gene and protein of retinoblastome RB.

4. NO.

5. Free radicals.

6. Oxidants.

7. Ca, Pb and other genotoxic agents.

8. Growth factors lack or absence.

9. Hormones – estrogens in male sexual glands, androgens – in female.

10. Immediate genes of early reaction (c-fos, c-myc, c-jun).

11. Sufficient Ca-ions amount.

12. Sufficient ATP level.

13. Bcl-2.

14. P53 deficiency.

Bcl-2 – (from engl. “B-cellular leukemia/lymphoma-2”) – oncogen, locating in long arm of 18^th chromosome (18q21), 3 exons. Proteins from 239 aminoacids. It is located in internal mitochondrial membrane, membranes of endoplasmic reticulum and nuclear membrane. There exists Bcl-2/Bax –rheostate: Bcl-2, Bcl-XL increasing lead to cellular survival; Bax, Bak, Bad increasing leads to death. Bcl-2 acts through peroxidative lipid oxidation inhibiting and Ca-ions level decreasing.

P53 – gene is in 17p13 (short arm of 17^th chromosome). Nuclear protein, M 53 Da, phosphoproteid with 53000 Da. 2 forms: supressor – more stable, inhibits proliferation in G1/S checkpoint of mitotic cycle and triggers apoptosis; mutant – less stable, inhibits apoptosis. At radiation – apoptosis inhibiting through protein p21.

Apoptosis role in physiological processes:

1. cells amount constancy support;

2. organism and its parts shape determining (embryogenesis and tissues involution);

3. providing correct correlation in different-typed cells;

4. genetically defective and senescent (old) cells removal;;

5. growth and terminal differentiation;

6. thymocytes and lymphocytes selection;

7. in synaptogenesis – excessive parts removal in the places of future synaptic clefts;

8. fingers formation in embryos;

9. endometrium functional layer removal at the beginning of menstrual bleeding and others.