5 reasons we need programmed cell death:
1) Harmful cells
2) Developmentally defective cells
3) Excess/unnecessary cells
4) Obsolete cells
5) Exploitation-chemotherapy
Define necrosis:
unregulated cell death associated with trauma + cellular disruption + inflammation
Define apoptosis:
programmed cell death-regulated cell death with controlled dissassembly of cellular contents no disruption
What happens to the organelles + cell in necrosis?
swell
What happens to the membrane in necrosis?
becomes permeable
When the cell lysis (explodes) in necrosis what is attracted and what does this cause?
phagocytes
inflammation
After necrosis has occured what happens?
neighbouring cells proliferate to cover gap
What are the 2 phases of apoptosis?
latent
execution
What happens in the latent phase of apotosis?
death pathways activated
cells still morphologically the same
What happens in the execution phase of apotosis?
organised disassembly of cell
membrane blebs
fragmentation into membrane-enclosed apoptotic bodies
Why is there no inflammation in apoptosis?
plasma membrane remains intact
How can you check if a cell is undergoing apoptosis?
DNA fragmentation
What are the types of cell death that have features of both?
Apoptosis like PCD
Necrosis like PCD
What is another key difference between necrosis + apoptosis?
Apoptosis requires energy to form apoptosome
So what can often determine which type of death a cell has?
Energy levels within the cell
What are the executioners of apoptosis called?
caspases
How are caspases activated?
proteolysis
What are the 2 types of caspases called?
initiator
effector
What are the 4 initiator caspases and what domains do they have?
2 + 9=CARD domains
8 + 10=DED domains
What sort of interactions do caspases have?
homotypic-protein interactions between same protein
What are the 3 effector caspases?
3 + 6 + 7
Caspases are synthesised to be……
Inactive zymogens (pro-caspases)
How are caspases activated?
Pro-domain + SS domains cleaved
Dimerisation
2 small + 2 large chains join to form active heterotetramer
How does caspases activate eachother?
Caspase cascade
How do initiator caspases trigger apoptosis?
By cleaving + activating effector caspases
How do effector caspases execute the apoptotic programme?
Inactivate proteins/complexes e.g. nuclear lamins
Activate enzymes e.g. protein kinases/nucleases
2 mechanism of initial caspase activation?
Receptor mediated pathway (extrinsic)
Mitochondrial death pathway (intrinsic)
What do death receptors use to recruit other proteins?
adapter proteins
What are the other proteins death receptors recruit and what do they do?
FADD-activates receptor mediated apoptosis
FLIP-inhibits
What domains is FADD vs FLIP adapter protein made of?
FADD=DED +DD
FLIP=DED + DED
Sumarise how receptor mediated apoptosis is triggered:
Fas-L on lymphocytes binds to death receptors
FADD recruited
Procaspase 8 binds to FADD
They transcleave eachother to activate caspase 8
active caspase 8 tetramer released
How does FLIP adapter protein inhibit apoptosis?
competes with FADD for binding=pro-caspase 8 not activated
How can mitochondria activate caspases and then apoptosis?
Mitochondria are very sensitive to cellular stresses so lose membrane potential and mitochondrial proteins are released triggering formation of apoptosome
What 4 things make up apoptosome?
ATP
pro-caspase 9
Alaf-1
cytochrome C
How is mitochondrial apoptosis linked to receptor mediated pathway?
Caspase 8 which has been activated by death receptors cleaves BID which enhances mitochondrial protein release
How is mitochondrial dependent apoptosis regulated?
Bcl-2 proteins e,g, BID
What stimulates release of Bcl-2 proteins?
PI3 kinase
What do PKB/Akt do?
block apoptosis
What does PTEN do?
Counteracts PI3-K signalling
