Apoptosis

Question 1

What is apoptosis?

Answer 1

Programmed cell death

Question 2

What is tissue homeostasis?

Answer 2

The balance between proliferation and cell death

Programmed cell death is an important part of normal tissue physiology e.g. in development, the immune system & the nervous system

Question 3

What is necrosis?

Answer 3

Spilled cellular contents cause inflammation

Question 4

What happens in apoptosis?

Answer 4

Cells are digested from the inside then phagocytosed

Question 5

Describe normal apoptosis

Answer 5

• Responsible for elimination of cells during normal embryonic development
• Involved in cell turnover in healthy adult tissues
• Involved in physiological involution and atrophy of various tissues

Question 6

Describe pathological apoptosis

Answer 6

• Can be triggered by toxins
• Occurs spontaneously in untreated cancers
• Contributes to chemotherapy-induced tumour regression

Question 7

Structural changes in apoptosis

Answer 7

Occurs in 2 stages

• Nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments
• These apoptotic bodies are shed from epithelial lined surfaces or are taken up by other cells where they undergo a series of changes within phagosomes and are rapidly degraded by lysosomal enzymes

Question 8

The 2 pathways of apoptosis

Answer 8

Extrinsic = External signals such as ligand binding

Internal = internal stress or something like UV light

Both pathways converge to cause caspase activation where a family of proteases then digests the proteins & DNA

Question 9

Intrinsic apoptosis pathway

Answer 9

Mitochondria are the heart of apoptosis

Upstream events = Formation of pores in the outer mitochondrial membrane

Downstream events = Cytochrome C is released into the cytoplasm

Question 10

Steps of cytochrome C release

Answer 10

1. Cytochrome C is released from the mitochondria into the cytosol
2. Membrane asymmetry is lost = internal marker is externalised
3. Membrane integrity is lost (more permeable) = DNA dye enters cell

Question 11

Caspase activation in the downstream events

Answer 11

1. Cytochrome C is released
2. Apoptosomes assemble
3. Caspase activation
4. Proteolysis of substrates
5. DNA digestion

Question 12

Upstream events of apoptosis

Answer 12

Pro death factors (open the pores) and pro survival factors (keep pores closed) try to inhibit each other

Apoptotic stimulus favours the pro-death factors which can then activate the pore forming proteins and cause p53 to inhibit the pro-survival factors which

Question 13

Examples of pro-death factors

Answer 13

BID

BIM

BAD

NOXA

HRK

Question 14

Examples of pro-survival factors

Answer 14

BCL2

BCL-X

MCL1

Question 15

Examples of pore forming proteins

Answer 15

BAX and BAK

Question 16

Key thing about pro-survival factors

Answer 16

Drugs that inhibit pro-survival factors can sensitise cancer cells to chemotherapy

Question 17

Role of Bcl-xL

Answer 17

Bcl-xL is a pro-survival factor

Bcl-xLi is an inhibitor that competes with the pro-death factor

Question 18

How can cancer cells be sensitised to chemotherapy?

Answer 18

Bcl-xL inhibitor sensitises cancer cells to taxol-induced apoptosis

Taxol gives apoptotic stimulus and is enhanced by inhibiting pro-survival function

Question 19

Elimination of T cells that recognise ‘self’ antigens

Answer 19

• T cells that recognise ‘self’ antigens must be eliminated
• APC = antigen presenting cell
• If T cell binds an APC expressing ‘self’ then FasL is expressed (triggers extrinsic pathway)
• FasL then binds to its own Fas receptor, inducing apoptosis
• Defects in the Fas pathway cause autoimmune syndrome