Apoptosis

1. Apoptosis
Mohammed Fathy Bayomy, MSc, MD
Lecturer
Clinical Oncology & Nuclear Medicine
Faculty of Medicine
Zagazig University

2. Apoptosis
 Definition: Apoptosis is defined as a distinctive active, genetically
programmed cell death which eliminates unwanted cells. Literally,
apoptosis in Greek language means falling of leaves of trees in winter
 Character
* May be physiological or pathological
* Resulting from mild injuries
* Affects single isolated cells
* Nonviable cell constituents shrink &
are enclosed by cell membranes, 
absence of inflammatory reaction

4.  Pathogenesis: enzymes are activated by calcium ions, cytochrome-C,
Apaf-1 & ceramide
* Enzymatic cleavage of cytoskeleton protein by cysteine proteases
(caspases)
* Protein cross-linking by transglutaminases
* Cleavage of DNA by several agents, including enzymes
endonuclease
 Pathways: two enzymes activation pathways
1) Extrinsic (Death receptor) pathway
FAS ligand (soluble or membrane-bound) will bind to FAS cell
membrane receptor or cytokine tumor necrosis factor (TNF) will bind to
its receptor (TNFR) on cell membrane  activation of membrane-bound
protein FADD  caspase activation

5. 2) Intrinsic (Mitochondrial integrity) pathway
Increase of mitochondrial permeability  release of calcium &
cytochrome-C from mitochondria to cytosol  assembly of apoptotic
protease activating factor (Apaf-1)  activates caspases

6. Genetic control of Apoptosis
 Bcl-2 family members are decision-makers that integrate pro-apoptotic
and anti-apoptotic signals to determine whether cell should commit
suicide
1) Anti-apoptotic Bcl-2 type proteins
* Including Bcl-2, Bcl-xL, Bcl-wL
* Two ways of antagonizing death signals
- They insert into outer mitochondrial membrane to antagonize
channel-forming pro-apoptotic factors  cytochrome c release
- Bind cytoplasmic Apaf so that it cannot form apoptosome complex

7. 2) Pro-apoptotic Bcl-2 type proteins
* Pro-apoptotic ion channel forming members (Bax, Bak, Bok,
Bcl-xs) when they dimerize with pro-apoptotic BH3-only members
in outer mitochondrial membrane, they form an ion channel that
promotes cytochrome c release rather than inhibiting it
* Pro-apoptotic BH3-only proteins (Bad, Bid, Bom/Bim) activates
pro-apoptotic family members (Bax) & inactivates anti-apoptotic
members (Bcl-2)