7. Family of Proteins- main executors of the apoptotic
process.
They belong to a group of enzymes known as cysteine
proteases.
Caspase 8 and 10- initiator (extrinsic)
Caspase 9- initiator (intrinsic)
Lead to effector caspase 3 and 6
Cleave key cellular proteins
8. DNA damage within the cell.
Cancerous cells
Cells of the immune system after they have fulfilled their
function
Ionizing Radiation
Stress and infection such as virus
Types of Induction:
Cell surface death receptor mediated pathway (extrinsic)
Mitochondrial-initiated pathway (intrinsic)
9.
10. TNF alpha, FAS ligand bind with its specific transmembrane receptor present on
cell surface
Activates its intracellular death domain, which recruits adaptor protein with death
effector domain like FADD (fas associated death domain) and TRADD
FADD then associated with procaspase8 via dimerization of death effector domain
At this point DISC (Death inducing signaling complex) is formed and activate
caspase 8
COMMON PATHWAY
11. BCL2 Proteins:-
1.BH123 (pro apoptotic gene) = bax and bak
2. BCL2 ( anti-apoptotic gene) = Bcl2,Bcl-XL
3. BH3 only ( pro apoptotic gene) = bad,bim,bid,puma,noxa
12. DNA damage
ATM & ATRP sense the DNA damage and phosphorylate an enzyme cheakpoint
kinase 1 & 2
This cheak point kinase add a phosphate group on p53 protein
Activate pro apoptotic gene (bak,bax,bid,bad,noxa,puma)
Puma / Noxa protein bind to anti apoptotic bcl2 protein
Allow the binding of bak and bax and forming channel by which cytochrome C come
out into cytosol
Cytochrome C recruits apaf-1 (apoptotic protease activation factor) which recruits
procaspase 9 this together called apoptosome
14. Viral infection
The small pieces of viral protein complex with MHC-1 molecules and express on the
surface of the cell
T cytotoxic cells come to infected cell, they will recognize the viral proteins with the
help of TCR and help of another molecule CD8,T cell will concern that is the antigen is
associated with class 1 MHC molecules or not
If molecules are associated with class 1 MHC molecules then TCR and CD8 both are
activated and give signal to the cell through CD3 molecule
Activated T cell release peptide chain which produce perforins on the surface of the
infected cell
15. Then T cytotoxic cell release granzymes and this granzymes enter into cell through
this pores
This granzymes activated executional caspases
COMMON PATHWAY
16. Initiator caspases (8,9,10)
Convert procaspase 3,6,7 to caspase 3,6,7
Activate Endonuclease CAD
Degrades chromosomal DNA and chromatin condensation
Executional caspases causes disintegration of the cells into apoptotic body
Phagocytosis by macrophages
20. Apoptosis eliminates damaged cells (damage => mutations
=> cancer
Tumor suppressor p53 controls senescence and apoptosis
responses to damage.
Most cancer cells are defective in apoptotic
response(damaged, mutant cells survive)
High levels of anti-apoptotic proteins
or
Low levels of pro-apoptotic proteins ===> CANCER
21. Aging --> both too much and too little apoptosis
(evidence for both)
Too much ---> tissue degeneration
Too little ---> dysfunctional cells accumulate
hyperplasia (precancerous lesions)
23. Albanese, Joseph, Nicholas D. Ionizing Radiation Alters Fas Antigen
Ligand at the Cell Surface and on Exfoliated Plasma Membrane-
Derived Vesicle: Implications for Apoptosis and Intercellular
Signaling. Yale University School of Medicine. Radiation Research
pg. 49-61 (2000)
Albert's, Bruce, Alexander J., Julian L., Martin R., Keith R., Peter W.
Molecular Biology of The Cell 4th Edition. Garland Science. pg.
1010-1014. Chiarugi and Markowitz. PARP-1--a perpetrator of
apoptotic cell death? Science 297, p. 2008
Almas an, Alex. Cellular Commitment to Radiation-Induction Apoptosis.
Department of Cancer Biology. pg. 347-350 Vol. 153 Issue 3
(March 2000)
Bruchhaus, Iris. Protozoan parasites: Programmed Cell Death as a
Mechanism of parasitism. Bernhard Nocht Inst. Trop. Medicine.
Trends in Parasitology 23, no. 8 (August 2007):376-383
Ejima, Kuniaki. Induction of Apoptosis in Placentas of Pregnant Mice
Exposed to Lipopolysaccharides: Possible Involvement of
Fas/Fas Ligand System. University of Occupational and
Environmental Health. Biology of Reproduction 62, 178-185 . 17
May 1999.