evading apoptosis Flashcards
what is apoptosis
programmed cell death which removes damaged, unwanted or diseased cells. it is highly regulated and does not damage neighbouring cells
2 examples of overactive apoptosis
neurodegeneration and immunodeficiency
2 examples of underactive apoptosis
cancer and inflammatory conditions
physiological use of overactive apoptosis in normal cells
returns cell population to normal after challenge
physiological use of underactive apoptosis in normal cells
allows cell accumulation (immune response)
what happens to the cell in necrosis
cell swelling, organelle disruption, nuclear swelling and plasma membrane rupture
what happens to the cell in apoptosis
cell shrinkage, organelles stay intact, chromatin condensation, plasma membrane integrity is kept
cons of necrosis
its messy so cell contents are leaked into surroundings, could cause signal issues
how long does it take for apoptosis to occur
30-120 mins
3 examples of where messages for intrinsic apoptosis come from
DNA damage, ER stress and hypoxia
example of where messages for extrinsic apoptosis come from
death receptors on surface of the cell
2 main apoptosis routes
intrinsic and extrinsic
where does the message come from in intrinsic apoptosis
inside the cell
where does the message come from in extrinsic apoptosis
outside the cell
where does the name Caspases derive from
Cysteine ASPartate specific proteASES
what do caspases do
cut a specific protein sequence, where they cut is defined by a tetrapeptide
what is a tetrapeptide
4 amino acids
what are inflammatory caspases responsible for
the maturation of pro-inflammatory cytokines
what are initiator caspases responsible for
starting the caspase cascade
what are effector caspases responsible for
cleavage of cell substrates and mediate cell killing
what are caspases produced as
inactive zymogens
how are the inactive zymogens activated
they need to have 2 cleavages
what are the different inflammatory caspases
1,4,5,11,12,13 and 14
what are the different initiator capsases
2 and 9, 8 and 10
what are the different effector/ executioner caspases
3,6 and 7
what happens to the initiator caspase as a result of the apototic signal
dimerization, activation and cleavage
what does the active initiator caspase do
cleaves the executioner caspase
what does the active executioner caspase do
cleaves multiple cell substrates to cause cell death (apoptosis)
what do caspases do to cause cell death
they cleave structural proteins and DNA replication/repair enzymes
what is ICAD
inhibitor of caspase-activated DNase
normal function of PARP and consequence of inactivation
DNA repair, Disabled DNA repair
normal function of DNA-RC and consequence of inactivation
DNA rep, halt DNA rep
normal function of FAK and consequence of inactivation
regulate cell adhesion, cell detachment/migration
normal function of NuMA and consequence of inactivation
nuclear integrity, nuclear disassembly
normal function of α-fodrin and actin and consequence of inactivation
cytoskeleton, disassembly of cell structures
what does intrinsic apoptosis cause
mitochondrial damage perturbation which causes cytochrome C release
what happens in mitochondrial perturbation
the membrane changes and pores form, there is a loss of mitochondrial membrane potential that causes cytochrome C release
what happens after Cytochrome C release in intrinsic apoptosis
the messenger binds to inactive APAF-1 and activates it which activates pro-caspase 9
what is an apoptosome
an accumulation of APAF-1s
What does the Bcl-2 family do
govern mitochondrial permeabilisation, they can promote or inhibit apoptosis
what makes a protein part of the Bcl-2 family
all contain Bcl-2 homology domains , its not that they all have the same function
2 different types of Bcl-2 proteins
Anti-apoptotic and pro-apoptotic
anti-apoptosis Bcl-2 members
essential to life, if you get rid of them then cell populations reduce through apoptosis
pro-apoptosis Bcl-2 members: effectors
form pores in mitochondria to release cytochrome C (BAK, BAX)
pro-apoptosis Bcl-2 members: BH3
central to life and death decisions of the cell and activation during cell stress will dictate the outcome m
when do cell surface receptors transmit a signal in extrinsic apoptosis
once the ligand has bound
what happens when the ligand has bound in extrinsic apoptosis
the receptor recruits an adaptor protein which then activates a caspase resulting in a DISC
what is a DISC
death inducing signalling complex
in extrinsic apoptosis, what family are they receptors part of
Tumour necrosis factor receptor superfamily (TNFR)
what does the TNFR superfamily include
TNFR, FAS receptor, TRAIL receptor 1&2
what components are the TNFR receptors made of
it has a specific ligand, cytoplasmic region called a death domain (inside cell)
what complicates death receptor mediated cell death
decoy receptors
what supresses death receptor mediated cell death
FLIP
overview of phagocytosis
phagocyte englufs particle for form phagosome for same packaging, anti-inflammatory allows adaptive immune responses to cell derived material, find me eat me signalling
Evading apoptosis as a hallmark of cancer, why is it fundamental
cells dont die so they accumulate, they also fail to respond to treatment
how cancer evades apoptosis - impaired receptor signalling pathway
reduced expression of death receptors, expression of decoy receptors (no death domain present) or death signals (ligands) so cell doesn’t get message to die
how cancer evades apoptosis - disrupted balance of Bcl-2 family
overexpression of the anti-apoptotic proteins, underexpression of pro-apoptotic proteins (pores on membrane dont form)
3 other ways that cancer evades apoptosis
reduced expression of caspases, increase expression of IAPs, defects/mutations in p53
what does redundancy mean
theres multiple ways the cancer can take advantage of pathways e.g. in apoptosis, if one way doesn’t work it can do the others
what happens with p53 loss
there is a reduction in apoptosis caused by cell stress or DNA damage
how does p53 effect the Bcl-2 family
induces BH3-only proteins and allows function of effectors (Bax and Bak)
