mechanisms of disease II Flashcards
what are the functions of necrosis
removes damaged cells from an organism
failure to do so = chronic inflammation
necrosis causes acute inflammation to clear cell debris via phagocytosis
causes of necrosis
lack of blood supply
injury infection cancer infarction inflammation
necrosis step by step
- result of an injurious agent or event
- initial events are reversible, later ones aren’t
- lack of oxygen prevents ATP production
- cells swell due to influx of water (ATP required for ion pumps to work)
- lysosomes rupture, enzymes degrade other organelles and nuclear material haphazardly
- cellular debris released, triggers inflammation
microscopic appearance of necrosis
- nuclear changes
nuclear changes =
- chromatin condensation/shrinkage
- fragmentation of nucleus
- dissolution of chromatin by DNAse
microscopic appearance of necrosis
- cytoplasmic changes
- opacification = protein denaturation and aggregation
2. complete digestion of cells by enzymes causing cell to liquify
microscopic appearance of necrosis
- biochemical changes
- release of enzymes such as creatine kinase or lactate dehydrogenase
- release of other proteins such as myoglobin
functions of apoptosis
- selective process for deletion of superfluous infected or transformed cells
involved in:
- embryogenesis
- metamorphosis
- normal tissue turnover
- endocrine dependent tissue atrophy
- variety of pathological conditions
apoptosis step by step
- programmed cell death of one or a few cells
- events are irreversible and energy dependent
- cells shrink as cytoskeleton is disassembled
- orderly packaging of organelles and nuclear fragments into membrane bound vesicles
- new molecules are expressed on vesicle membrane that stimulate phagocytosis without inflammatory response
appearance of apoptosis
- cytoplasmic changes
- shrinkage of cell. organelles packaged into membrane vesicle
- cell fragmentation. membrane bound vesicles bud off
- phagocytosis of cell fragments by macrophage and adjacent cell
- no leakage of cytosolic components
appearance of apoptosis
- nucelar changes
- biochemical changes
- nuclear chromatin condenses on nuclear membrane and DNA cleavage
- expression of charged sugar molecules on outer surface of cell membranes and protein cleavage by proteases, caspases
difference of survival vs apoptosis
survival:
- cell-cell or cell-matrix contacts
- growth factors
- cytokines
apoptosis:
- disruption of cell-cell or cell-matrix contacts
- lack of growth factors
- DNA damaging agents
- death domain ligands
what are caspases
point of convergence for causes of apoptosis
caspases are cytosine protases
caspases form activation cascade, where one cleaves and one activates the next
death by a thousand cuts: substrates and functions
Lamin A and B = nuclear envelope
PARP = DNA repair
DNA-PK = DNA repair
topoisomerase II = DNA replication
Raf-1 = signalling
Akt/PKB = cell survival
STAT1 = signalling
elf4 = translation
effect of caspase activation
results to characteristic morphological changes
includes shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blabbing
how do we activate the initiator caspases
- initiator caspases activate themselves when in close proximity
- activation = bringing initiator caspases together
describe extrinsic apoptosis
induced by ligand binding to receptors causing receptor dimerisation
ligand induced multimerisaion - the players
- receptor
- death adaptor
- procaspase-8
describe TNF as an example
- tumor necrosis factor
- tumour necrosis factor receptor
- FAS-associated protein with death domain
- procaspase-8
auto proteolysis
describe intrinsic apoptosis
induced by cytochrome c released from mitochondria
describe cytochrome C
mitochondrial matrix protein
known for many years to be released in response to oxidative stress by permeability transition
any inducers of permeability transition also eventually induce apoptosis
cytochrome c induced apoptosis: the players
- cytochrome c
- procaspase-9
how is the release of cytochrome c from the mitochondria regulated
- a pore made of BCL-2 family proteins
- BCL 2 proteins can be pro or anti-apoptotic
anti-apoptotic (bcl-2, bcl-XL, others) = repress cytochrome c release
pro-apoptotic (Bax, bad, bid, others) = facilitate cytochrome c release
- some are not membrane proteins
- all have BH3 domain used to form dimers
if BCL-2 family proteins regulate cytochrome c release from mitochondria , what regulates BCL-2 proteins?
transcription driven by TP53
