Alternative cell death mechanisms Flashcards
(29 cards)
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
