CFM 2: Cell Death

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CFM 2: Cell Death
2015-09-10 17:15:53
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  1. Apoptosis vs. Necrosis
    • Apoptosis: active process, cellular shrinkage, intact membrane, nuclear condensation, phagocytosis of cell corpse
    • Necrosis: passive process, cell swelling, membrane rupture
  2. 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)
  3. Apoptosis yields distinct DNA fragmentation bands of ______ bp intervals
  4. 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)
  5. CAD
    • DNAse
    • Typically inhibited by ICAD
    • Caspase cleaves ICAD, so CAD cleaves DNA, making the hallmark DNA fragments of apoptosis
  6. Initiator vs. Effector Caspases; how are each activated?
    • Effector caspases: activated by initiator┬ácaspases
    • Initiator caspases: activated when brought into an oligomeric complex by upstream activators
  7. Two pathways to activate initiator caspases for apoptosis
    • Extrinsic
    • Intrinsic
  8. 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
  9. 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┬ácomplex with caspase 9
    • This activates caspase 3
  10. 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
  11. IAPs
    • Inhibitor of Apoptosis Proteins
    • Inhibit cell death by directly binding caspases (blocking apoptosis at the last step)
  12. Smac
    IAP antagonist
  13. When cytochrome C is released from mitochondria, what else gets released?
  14. p53 and apoptosis
    p53 initiates transcription of BH3 only proteins
  15. TNFalpha
    Activates a necrosis pathway
  16. MLKL
    In response to TNF alpha, MLKL (a pseudokinase) punctures holes in the membrane for necrosis