Lecture - Apoptosis

1. Apoptosis: Programmed Cell
Death
A matter of life or death for cells!
(Greek for ‘falling off’)

2. Apoptosis
• Apoptosis is a form of programmed cell death, or
“cellular suicide.” It is different from necrosis, in
which cells die due to injury.
• Apoptosis is an orderly process in which the cell’s
contents are packaged into small packets of
membrane for “garbage collection” by immune cells.
• Apoptosis removes cells during development,
eliminates potentially cancerous and virus-infected
cells, and maintains balance in the body.

3. Why do multicellular organisms need to
regulate the death of their cells?
To allow body structures to grow and develop correctly.
To remove body structures that are no longer required.
To regulate the sizes of cell populations in adult bodies cell proliferation
must be balanced with cell death.
This allows organisms to precisely control the sizes of their tissues and
organs.
To prevent cells from surviving in environments where they should not be
present.
To kill cells that have been infected by pathogens.
To prevent the survival of cells with damaged DNA (these have the
potential to become cancerous).
To eliminate white blood cells that would produce an immune response to
the body’s own cells.

6. The two forms of cell death

9. Why do multicellular organisms need to
regulate the death of their cells?
• To kill cells that have been infected by
pathogens.
• To prevent the survival of cells with damaged
DNA (these have the potential to become
cancerous).
• To eliminate white blood cells that would
produce an immune response to the body’s own
cells.

11. Apoptosis compared to necrosis: What
happens to the cell when it dies?
Feature Apoptosis Necrosis
Regulated by organism Yes: involves a series of
enzyme-controlled reactions
No: can occur as a result
of injury
DNA broken down Yes Only after cell has lysed
Cell membrane
disintegration
No Yes
Nuclear membrane
broken down
Yes No
Number of cells affected May be single cells Usually sheets of cells
Energy requirement ATP dependent (active
process)
Energy input not required
(passive process)
Fate of dead cells Ingested by neighbouring cells
or phagocytes
Ingested by phagocytes
Leakage of cell contents No Yes
End point Cell fragments into smaller
bodies
Lysis of whole cell

12. The mechanism of apoptosis
1. Activation of procaspase proteins
Active
caspase B
Active
caspase A
Inactive
procaspase
Prodomain

13. The mechanism of apoptosis
2. Caspase activation cascade
Active
caspase A
Active caspase B
Active caspase C

14. The mechanism of apoptosis
3. Caspases are proteinases: they cleave key cell
proteins
Inactive
DNAse
Active
DNAse
Nuclear
lamins
Fragmented
nuclear lamins
Gelsolin Actin-digesting enzyme
Caspase activity

15. The mechanism of apoptosis
4. Caspase activity results in the controlled destruction
of the cell
Active DNAse
Breakdown of
nuclear DNA
Fragmented nuclear
lamins
Disassembly
of nucleus
Actin-digesting enzyme Disassembly of
cytoskeleton

16. Initiation of apoptosis: the death signal
• Adaptor proteins cause initiator procaspases to
cluster together.
• Clustering induces a conformational change that
activates the procaspases.
Caspase activation Caspase
cascade

17. Intracellular death signals
• Mitochondrion-mediated pathway
1. Damaged mitochondrion
3. Caspase
cascade
2. Cytochrome C
protein released

18. Intracellular death signals
• DNA damage can trigger apoptosis via the p53
protein.

19. Damaged
DNA
Caspase cascade
Increased
concentration of
p53 protein in
cell
Increased
transcription of
genes that code
for proteins that
activate
procaspases
Increased
protein kinase
activity

20. Extracellular death signals: survival
factors
• Animal cells undergo apoptosis if they are deprived of
survival factors released by other cells.
• This ensures that cells only survive in locations where
they are needed, when they are needed.
• The default program for most cells is suicide!

21. Extracellular death signals: inhibitory
signal proteins
- Some signal proteins oppose the effects of
growth factors and survival factors. They can
inhibit the growth of organs by stimulating
apoptosis.
- For example, mouse limb formation (see earlier
images D, E, F and G).

22. Extracellular death signals
• Body cells infected with certain pathogens,
eg some viruses, present fragments of
antigenic proteins on surface receptor
proteins on their cell membranes.

24. Extracellular death signals
• Activated killer T lymphocytes can
recognise body cells displaying antigens.
The lymphocytes bind surface receptor
proteins on the target cell and trigger
apoptosis.

25. Animation

26. Putting it together

27. Initiation of apoptosis by killer T lymphocytes
Target cell
Lymphocyte

28. Initiation of apoptosis by killer T lymphocytes
Target cell Caspase cascade

29. Which cellular events could cause the
control of apoptosis to be impaired?

30. What could be the consequence of
impaired apoptosis to:
(a) the affected cell?
(b) the organism containing the
affected cell?

31. Cancer
• The development of some forms of leukemia is
promoted by the loss of control of apoptosis.
• Mutations to the DNA of B lymphocytes can
cause them to produce abnormally large
quantities of a protein that inhibits apoptosis.
• p53 is a cancer-critical gene.

32. 3. Inhibition of
procaspase
activation
4. Cell develops
resistance to
apoptosis
5. Survival of B
lymphocytes that would
normally have died
1. Chromosome
translocation
2. Over-expression
of a regulatory
protein