PHRD5015 Lecture 8 - Programmed cell death & autophagy

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PHRD5015 Lecture 8 - Programmed cell death & autophagy
2013-09-28 15:12:29
Programmed cell death autophagy

Programmed cell death & autophagy
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  1. ordered process of cell disassembly
  2. sudden death/lysis of the cell
  3. physiological reasons for cell death (2)
    • 1) development
    • 2) turnover
  4. cellular changes during apoptosis
    • cell condenses
    • cytoskeleton & nuclear envelope break down
    • cell breaks into apoptotic bodies & are removed by macrophages
  5. family of proteins that mediate apoptosis
  6. how are caspases activated?
    by cleavage (removal of inhibitory pro-domain, then cleaved into large & small subunit)
  7. caspase directly associated with the signaling machinery which activates apoptosis
    initiator caspase
  8. how is the initiator caspase activated?
  9. 3 important caspase targets
    • 1) actin
    • 2) laminin
    • 3) ICAD
  10. protein that is part of the nuclear scaffold
  11. protein that inhibits DNase
    ICAD (inhibitor of the caspase-activated DNase)
  12. do caspases degrade DNA?
  13. extrinsic apoptotic pathway
    • signal to initiate apoptosis comes from an outside source
    • (ex: Fas)
  14. initiator caspases for the extrinsic apoptotic pathway
    caspase 8
  15. 3 death receptors
    • 1) Fas
    • 2) TNFR1
    • 3) TRAILR1, TRAILR2, DR6
  16. how are death receptors activated?
    by clustering
  17. apoptotic receptor associated with heart disease
    Fas in cardiomyocytes
  18. intrinsic apoptotic pathway
    signal for apoptosis is initiated by the cell itself
  19. organelle that initiates the apoptotic signal
  20. most notable pro-apoptotic factor in mitochondria
    cytochrome c
  21. initiator caspase involved in the intrinsic apoptotic pathway
    caspase 9
  22. steps in the intrinsic pathway
    • mitochondrial membrane releases cyt c -> cyt c induces aggregation of Apaf-1 -_ Apaf-1 recruits and activates casp9
    • cyt c + Apaf-1 + casp9 = scaffold
  23. Bax
    pro-apoptotic (pore forming) protein involved in the intrinsic pathway
  24. Bcl-2
    anti-apoptotic (inhibitory) protein involved in the intrinsic pathway
  25. how do anti-apoptotic proteins function?
    sequester the propapoptotic proteins to prevent pore formation
  26. conserved domain present in the Bcl-2 family members that function as stress sensors and promote activation
  27. major phagocytic cell type engaged in clearing apoptotic cells
  28. "eat me" signal for macrophages
    phosphatidyl serine
  29. where is phosphatidyl serene normally found?
    in the inner leaflet of the bilayer
  30. what happens to apoptotic cells that are not phagocytosed?
    undergo necrosis and release material that can activate an immune response and increase the likelihood of self-directed antibodies being produced
  31. deficits in what process has been implicated in autoimmune disease (SLE in particular)?
    macrophage phagocytosis of apoptotic bodies
  32. phosphatase activated by Ca2+ that can activate the intrinsic pathway
  33. important functions of Ca2+ in cell death (3)
    • 1) taken up by mitochondria & inhibits ATP synthesis
    • 2) promotes dissociation of actin filaments from the plasma membrane
    • 3) activates other hydrolytic enzymes
  34. protein that senses DNA damage
  35. first response of p53
    induce genes that will arrest the cell cycle
  36. if DNA repair is unsuccessful, what does p53 do?
    induces transcription of apoptosis activators in the Bcl-2 family
  37. what defines ER stress?
    accumulation of protein aggregates
  38. ER stress sensor
  39. what happens if after prolonged IRE1 activation?
    activation of the intrinsic pathway through BAX activation and Bcl-2 inhibition
  40. 5 characteristics of necrosis
    • 1) cell swelling followed by explosion
    • 2) mitochondrial dysfunction
    • 3) ATP degradation
    • 4) release/activation of lysosomal enzymes
    • 5) release of "danger signals"
  41. what leads to the recruitment of inflammatory signals which cause further damage?
    release of danger signals
  42. process whereby the cell obtains necessary nutrients during times of nutrient deprivation
  43. specific proteins activated to promote the creation of a special lysosome-like structure
  44. structure of autophagosome
    • bilayered
    • outer membrane fuses with a lysosome
    • contents of inner membrane then degraded
  45. multi protein kinase which promotes the extension of membrane to create the autophagosome
    ULK complex
  46. how is the ULK complex regulated?
    negative regulation by mTOR
  47. transmembrane proteins which play multiple roles in the formation and fusion of autophagosomes
    ATG proteins
  48. how are ATG proteins regulated
    SIRT1 deacetylates and activates them
  49. purpose of autophagy
    recycle damaged cellular organs