Apoptosis

Question 1

Summarise apoptosis

Answer 1

Condensation and segmentation of nuclei with fragments of chromosomal DNA into nucleosome fragments.
DNA fragmentation by endonucleases/DNAses.
Enzymes are able to access sites between the nucleosomes
Cell cycle regulators, DNA repair components, Cell signalling and adhesion molecules, cytoskeleton
Cytoplasm begins to shrink following cleavage of laminins and actin. Organelles compact. Chromatin condenses.
Membrane changes such as the translocation of phosphatidylserine from the inner leaflet of the cell to the outer surface.
Blebbing and fragmentation.
Separation of cell fragments into apoptotic bodies.
Apoptotic bodies allow for easy clearance by macrophages, with no IR.

Question 2

Compare necrosis to apoptosis

Answer 2

Apoptosis - from external or internal signals, energy dependent, single cells, cells shrink and are engulfed, normally no inflammation
Necrosis- ischemia/toxins/radiation, groups if cells, cells swell and burst, marked inflammation

Question 3

Describe the mechanism of apoptosis

Answer 3

Bcl2 is repressed, allowing the release of pro-apoptotic activators - caspases (cysteine proteases)
Extrinsic pathway (i by FLIP)- ligand binds to and activate death R. FADD adapter protein activated. Activation of caspsases.
Intrinsic pathway - Intracellular stimuli caused by stress. Mitochondrial membrane potential change allows release of pro-apoptotic proteins into the cytosol: cytochrome C, Diablo and Omi. Activation of caspases. Cytochrome C release activates the scaffold protein Apaf1. Procaspase-9 clusters with them to form the apoptosome. This causes activation of Caspase-9. Caspase-8 activation causes cleavage of BID protein, which is pro-apoptotic. Cleaved BID causes mitochondrial damage and activation of the intrinsic pathway.
Granzyme pathway - activated by granules from Tc. Perforin and granzyme degrade cell

Question 4

What is the difference between the intrinsic and extrinsic pathways to apoptosis?

Answer 4

Intrinsic- mitochondrial response to apoptotic signal
Extrinsic- death ligand binds to death receptor to activate the caspase cascade eg. Fas and FasL recruit FADD activate caspase 8 and 10

Question 5

How do cell stress signals activate apoptotic pathways?

Answer 5

DNA damage activates p53 which can lead to the activation of the caspases cascade by the mitochondria and cytochrome C

Question 6

What is the relationship between cancer and apoptosis?

Answer 6

Apoptotic pathways are suppressed in cancer and survival pathways are activated
Cancers can be treated by activating apoptosis

Question 7

What is autophagy?

Answer 7

Has roles in:
Antigen presentation
Survival during short term starvation
Organelle turnover
Protection against metabolic stress and DNA damage 
Clearance of aggregate prone proteins
Regulation of cell size
Longevity
Programmed cell death
Defence against intracellular pathogens
FoxO3, PTEN, reactive oxygen species, GTPase and low ATP act to promote autophagy
Ra's, PI3, Akt, mTOR act to promote autophagy

Question 8

Describe autophagy in cancer

Answer 8

Pro-tumour- escape from stress, tumour cell fitness, treatment resistance, dormancy
Anti-tumour- inhibits chromosomal instability, oxidative stress, inflammation and promotes senescence