Cell death Flashcards
How do cells die?
Necrosis:
- Mass death of cells at same time
- Caused by external signal damaging the cell
- Generally associated with physical damage e.g. burns and cuts
Apoptosis
- Very controlled singular at a time cell death
- Programmed
- 50 billion cells per day
- Can be caused by very precise external signals but mainly by internal signals
More than one of these can be involved in the death of a cell, isn’t exclusive
When does necrosis occur?
Physical damage
- Trauma e.g. cuts and burns
- Extreme temperatures e.g. frostbite
Toxins
- External e.g. snake venom
- Internal e.g. bacterial toxins
Acute hypoxia/ischaemia e.g. stroke
Cellular death then causes cell insides to spill out into surrounding area, this then causes very sever inflammatory response in nearby cells which when spread becomes dangerous
When does apoptosis occur
Occurs everywhere and is a key part of keeping the body functioning
Physiological situations:
- Tissue size maintenance
- Developmental cell loss - growth factors
- Removal of immune cells
- Hormone - dependent involution
- Inappropriate interactions - Anoikis (tells cells when they are in the wrong place and interacting with the wrong cells)
Pathological situations:
- DNA damage e.g. radiation, oxidative stress
- Virally infected cells
Characteristics of necrosis
Reversible:
- Membrane integrity compromised
- Organelle and cell swelling
Irreversible:
- Increased intracellular calcium
- Autolysis
- Cell bursting (cell lysis)
- Elicits an inflammatory response
Characteristics of apoptosis
Shrinkage
Nuclear breakdown
Apoptotic bodies
Phagocytosis
No inflammatory response (because there is no loss of membrane integrity)
Requires energy
Controlled cell death
Relationship with autophagy
Necrosis or apoptosis - brain ischaemia
Both may be involved in the death of cells during an event
Cells in middle die through necrosis
Cells at edge die through apoptosis
This restricts spread of cell death
Developmental apoptosis
C. elegans
Nematode worm
1 mm long with ~ 110 cells
131 die in development
Metamorphosis e.g. tadpole - frog
- Surge in thyroid hormone in the blood initiate apoptosis in tail cells
Digit formation in mice:
- Apoptosis is initiated through release of local signal proteins
Neuronal connections are refined by the competition for survival factors
Not enough survival factor = apoptosis
Ced genes
C-elegans provide good model for studying apoptotic pathways
Ced genes involved from recognition of apoptotic signal to engulfment of apoptotic cell by phagocytes
Manny c.elegans genes are conserved in mammals:
- EGL-1 -> BH3-only proteins
- Ced 9 -> Bcl-2
- Ced 4 -> APAF-1
- Ced 3 (apoptotic initiator) -> caspases
EGL-1 inhibits Ced 9 which inhibits Ced4 which promotes Ced3 which leads to death
Pro and anti apoptotic genes
- Decreases Ced 3 or 4 gives excess adult cells
- Decrease Ced 9 gives massive cell death
Caspases
The executioners of cell death = essential for apoptosis
C = cysteine at their active site
asp = aspartic acids are the cleavage site in target proteins
Irreversible pathway
10+ ced-3 homologues
Irreversible once started
Initiator and executioner caspases
Initiator caspases:
- Activated by apoptotic signals
- Activate executioner caspases
Executioner caspases:
- cleave >1000 proteins
Amplifying proteolytic cascade:
- one initiator caspase can activate multiple executioner caspases
Active caspase will then go on to cleave its targets of substrates
Some caspase targets
Causes breakdown of nucleus structure, including nuclear lamina through cleavage of nuclear lamins
Prevents DNA repair by cleaving DNA repair enzymes PARP (Poly ADP-ribose polymerase)
Cause cytoskeletal changes, e.g. the breakdown of actin, by cleaving cytoskeletal proteins like Gelsolin
There are two main ways of initiating apoptosis
Extrinsic pathway
Intrinsic pathway
Extrinsic pathway
Tumour necrosis factor family
6 related receptors - the death receptors
Indirectly (via the DISC activate initiator caspases
E.g.
- Apoptotic signal = Fas ligand on killer lymphocyte
- Caspase-8 = initiator caspase
- DISC = death-induced signalling complex
Fas ligand is what causes the extrinsic pathway of apoptosis to be activated
Intrinsic pathway
Triggered by:
- Stress signals e.g. DNA damage
- Developmental signals
Example
- Cytochrome C release from mitochondria
- Adaptor protein = Apaf-1 = apoptotic protease activating factor
- Caspase-9 = initiator caspase
Balance between pro and anti apoptotic factors known as Bcl2 family proteins
- EGL-1 homologue Bh3-only protein = pro-apoptotic
- Ced9 homologue Bcl2 protein = anti-apoptotic
Apoptosis pathways - simply summary
Activated by cell death inducing stimuli
Caspases cleave proteins involved in:
- Inhibiting apoptosis
- DNA repair
- Cell cycle
- nuclear structure
