Alternative cell death mechanisms Flashcards
what causes the activation of initiator caspases?
dimerisaton
which 4 capspases are initiator caspases?
1, 8, 9, 10
briefly, recap how cspase 9 is activated?
- cytochrome C released from mitochondria
- oligomerises APAF-1 to heptamer
- exposes CARD region
- binds to caspase 9 CARD region
- recruits to apoptosome
- dimerise
- caspase 9 cleaves off and goes on to activate executioner caspases
what is the recruitment of initiator caspase regulated by?
large pro-domains
what are TNFs?
Tumour Necrosis Factors
what are the binding domains of caspase 8? (2)
- death domain
- death effector domain
describe the activation of caspase 8
- ligand on cytotoxic T -cells binds to cell surface
- causes oligermerisation of FADd (Fas Associated Death domain)
- recruits caspase 8, as caspase 8’s death domain binds with FADd- forms DISC complex
- caspase 8 dimerises- activates
- cleaves itself off DISC
- active and free
what’s Acute Lymphoproliferative syndrome?
where there’s reduced apoptosis of leukocytes (which usually occurs to end inflammatory response), therefore a build up of leukocytes e.g. lymphoid tumour
- caused by mutation in FASL, CD95 or caspase 8
why can’t FasL be used in cancer treatment?
it’s apoptotic affects are too widespread- not specific enough
what other family of receptors can be used in cancer treatment?
TRALL receptors
what are the 2 important TRALL receptors?
DR4
DR5
what happens to DR4 + 5 in response to anti-cancer durgs?
their expression increases- causing apoptosis of tumour cells
what type of protein is Bid?
BH3
what is Bid a substrate of?
Caspase 8
what does Bid cause?
mitochondria to release cytochrome C and inhibit XIAP (apoptotic inhibitor)
generally, how are non-apoptic caspase activated?
- using NLRs
recruiting them to the inflammasome
pro-inflammatory response
what does caspase 1 activate?
IL1-B (interleukin)
is necrotic cell death passive or active?
passive- no ATP used
what does necrotic cell death release?
DAMPs
what causes necrotic death death (rather than apoptotic)?
ATP deprivation
there’s a loss of PM control/ osmoregulation– swelling
which areas are particularly energy hungry- rely greatly on ATP?
neurons
cardiac muscle
therefore are major sites of necrotic injury
how does Ischemia cause necrosis?
loss of BF- loss of ATP (no respiration)
cells in immediate area die from necrosis
what does reperfusion cause?
- loss of IC K+
- influx of Ca2+ - acidification
- depletes cellular energy
- mitochondria can react to reduced pH by opening permeability transition pore (PTP)- mitochondria bursts
how can necrotic cells induced apoptosis of their neighbours?
necrotic cells release ROS (reactive oxygen species) and DAMPs induces inflammatory response
- activating inflammatory cells produces death receptor ligands (e.g. T-cells) that can activate caspase 8
what happens during autophagy?
large vacuole forms- membrane stays intact
lysosomes degrade cell contents for nutrients
happens when cells are deprived of nutrients
what happens when cancer cells enter autophagy?
- makes them dormant, therefore harder to kill
what is Mitophagy?
phagocytosis of damaged mitochondria
what is parkinson’s disease characterised by?
loss of dopamine neurons in substantia nigra
how can mutations in PINK and Parkin cause parkinsons?
usually, they label mitochondria for autophagosome destruction
w/o there can be an accumulation of amaged mitochondria leading to neural death in substatia nigra
