CFM 2: Cell Death
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Apoptosis vs. Necrosis
- Apoptosis: active process, cellular shrinkage, intact membrane, nuclear condensation, phagocytosis of cell corpse
- Necrosis: passive process, cell swelling, membrane rupture
Cells undergoing apoptosis are degraded very rapidly. How do you detect these events?
- Morphology: condensed cells or nuclei
- TUNEL: DNA fragmentation (marking nicked DNA of apoptotic cells)
Apoptosis yields distinct DNA fragmentation bands of ______ bp intervals
Why is cell death necessary during development and normal homeostasis?
- To sculpt body structures during development
- To eliminate superfluous cells (e.g. neurons that do not make the right connections)
- To eliminate damaged and potentially dangerous cells (cells with DNA damage, self-reacting lymphocytes)
- Typically inhibited by ICAD
- Caspase cleaves ICAD, so CAD cleaves DNA, making the hallmark DNA fragments of apoptosis
Initiator vs. Effector Caspases; how are each activated?
- Effector caspases: activated by initiator caspases
- Initiator caspases: activated when brought into an oligomeric complex by upstream activators
Two pathways to activate initiator caspases for apoptosis
Mechanism of Extrinsic Pathway of Apoptosis
Death receptor activation (e.g. Fas), initiator caspase (caspase-8) brought into oligomeric DISC complex and cleaved to be activated, effector caspase (caspase-3) activated
Mechanism of Intrinsic Pathway of Apoptosis
- Various cell death stimuli activate BH3-only proteins
- These activate pro-apoptotic Bcl-2 proteins, which allow the mitochondria to release cytochrome C
- Cytochrome C binds Apaf 1 and forms multimeric complex with caspase 9
- This activates caspase 3
Bcl-2 family proteins
- BH3 only: proapoptotic, stimulated first to tip the balance towards BH123 by inhibiting anti-apoptotic Bcl-2
- BH123: proapoptotic, stimulate mitochondrial release of cytochrome C
- Anti-apoptotic Bcl2 protein: BH1234
- Inhibitor of Apoptosis Proteins
- Inhibit cell death by directly binding caspases (blocking apoptosis at the last step)
When cytochrome C is released from mitochondria, what else gets released?
p53 and apoptosis
p53 initiates transcription of BH3 only proteins
Activates a necrosis pathway
In response to TNF alpha, MLKL (a pseudokinase) punctures holes in the membrane for necrosis
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