Apoptosis Flashcards
Name the 3 types of cell death
Apoptosis
Necrosis
Autophagy
Describe the 3 types of cell death
Apoptosis
= Regulated cell death
= No spillage
Necrosis
= Entire cell burst
= Contents spill out
= Can have an inflammatory reaction
Autophagy
= Self-eating
= Acidified container in cells swell
What processes in the body is significantly apoptosis involved in?
Oocyte development Immune system activation Disease: -> cancer (too little) -> Alzheimer's (too much)
Describe the process of apoptosis
1) DNA fragmentation
Chromatin condensation
Membrane blebbing (outgrowths)
Cell shrinkage
2) Fragmentation
Disassembly into apoptotic bodies
3) Engulfment by neighbouring cellsWhat are the neighbouring cells that engulf dead cells that were killed by apoptosis?
Phagocytes
What are the triggers of apoptosis?
Extrinsic:
= Death receptors (e.g. TNF (tumour necrosis factor))
= Growth factor withdrawal (EPGF)
= Loss of contact w/ surroundings
Intrinsic:
= Irreparable internal damage (DNA damage)
= Conflicting signals for cell division
What are the regulators of apoptosis?
p53
Bcl-2 family
What are the executioners of apoptosis?
Apaf-1
Caspases
What does caspases stand for?
Cysteinyl aspartate specific proteases
Name 4 key features of caspases
1) Highly specific
2) Recognition of at least 4 amino acids N-terminal to the cleavage site
3) Variable N domain regulates activation
4) All domains derived from inactive precursor by cleavage specific sites
How do caspases disassemble a cell?
Inhibition of anti-apoptotic proteins (bcl-2)
Breakdown cell structures (e.g. nuclear lamins -> DNA breakdown)
What initiates + controls intrinsic signalling pathways of apoptosis?
Initiated by conflicting cell division/irreparable DNA damage signals
Controlled by intracellular Bcl-2 protein family at mito.
What initiates + mediates extrinsic signalling pathways for apoptosis?
Initiated by growth factor withdrawal, radiation, chemicals …
Mediated by members of TNF receptor
What is FADD?
Fast activated death domain
Intracellular domains of TRAIL receptors
Activates initiator caspase 8
What are IAPs?
Inhibitors of apoptosis proteins
Work at multiple sites of signalling pathway
Describe an extrinsic signalling pathway of apoptosis (hint: TRAIL)
1) TRAIL ligand binds to a TRAIL receptor (TRAILR1 or TRAILR2) -> trimerisation of receptors
2) FADD (domains) brought close together -> activates cascade of signalling molecules (one being caspase 8)
3) Activated initiator caspase 8 activates executioner caspase 3
4) Caspase 3 targets intracellular components -> apoptosis
Describe a internal signalling pathway of apoptosis
1) Active caspase 8 activates/truncates BID (protein) to form active tBID (pro-apoptotic)
2) tBID inhibits BCL2 (on mito.) + BCL2 inhibits BAX + BAK (on mito.)
3) tBID also activates BAX + BAK (pro-apoptotic)
4) Makes mito. membrane more porous (MOMP = mitochondrial outer membrane permeabilisation)
5) Molecules (e.g. cytochrome c + DIABLO) leak out of mito.
6a) Cytochrome c activates APAF (protein) -> forms apoptosome -> activates caspase 9 -> activates caspase 3 -> apoptosis
6b) DIABLO inhibits the IAPs -> activates caspase 9 -> activates caspase 3 -> apoptosis
BCL-2 protein family includes what protein?
Anti-apoptotic:
= BCL-2
= BCL-B
= BAL-X1 …
Pro-apoptotic:
= BAX + BAK
Pro-apoptotic initiators (BH3 only):
BID
How do cancer cells avoid apoptosis?
Over-expression of anti-apoptotic proteins (e.g. BCL-2)
and/or
Over-expression of pro-apoptotic protein inhibitors/mutations in pro-apoptotic genes (e.g. BAX + BAK)
Not all tumour cells survive (survival of the nastiest)
What types of cell death are involved in cancer/tumours?
Apoptosis
Autophagy
