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The Biology of Cancer Chapter 9:
p53 and Apoptosis: Master Guardian and Executioner
Cell Death
Apoptosis Autophagy Necrosis
Programmed
cell death.
Death cycle is
programmed
by the cell itself
‘Self-eating’
Catabolic p...
The term was originally used by
Wyllie and his colleagues and is from
the Greek meaning “dropping away”
as the leaves from...
Active cell death
• Specific gene expression
• Specific intracellular signals
• Requires energy and RNA and protein synthe...
Figure 9.18d The Biology of Cancer (© Garland Science 2007)
An apoptotic cell
showing fragmented
Golgi bodies (green)
Autophagy
Srcf.ucam.org
Autophagy: clearing out garbage
The Face of Cell Death: Apoptosis
Two Apoptotic Pathways: Extrinsic & Intrinsic
Two Pathways that Initiate Apoptosis
Intrinsic/ Mitochondrial Apoptosis
Regulated by Mitochondrial
Cytochrome C release
Ex...
Two Pathways that Initiate Apoptosis
Intrinsic Pathway
Chemotherapy
Irradiation
Figure 9.29 The Biology of Cancer (© Garland Science 2007)
The Apoptotic Caspase Cascade: Apoptosome
The Wheel of Death
Pr...
Figure 9.28 The Biology of Cancer (© Garland Science 2007)
The Wheel of Death - Apoptosome
The apoptosome
is assembled in ...
The apoptosome
associates with Apaf1.
this causes the assembly
of the 7 spoked wheel
in which Apaf-1 forms the spokes
and ...
Caspase 9 activates the executioner caspases
Active caspase 9
Executioner caspases :
Caspase 3, 6 & 7 cleave
DNA by activating
DNAase
APOPTOSIS
Executioner caspases :
Caspase 3, 6 & 7 cleave DNA
by activating DNAase
APOPTOSIS
Caspase 9 is activated
Caspase 9 activat...
The Extrinsic Pathway: In
the extrinsic pathway, signal
molecules known as ligands,
which are released by other
cells, bin...
The Extrinsic Apoptotic Pathway
Disc (death inducing signal complex)
TRADD : tumor necrosis factor death domain, FADD: Fas...
Figure 9.19 The Biology of Cancer (© Garland Science 2007)
Apoptosis of cells forming webs between future mouse
toes. The ...
Apoptotic humor !
p53 and Apoptosis
Figure 9.8 The Biology of Cancer (© Garland Science 2007)
p53 - activating signals’s and p53 downstream effects
A variety ...
A cancer cell does not want to undergo
apoptosis hence it initiates
anti-apoptotic strategies
Figure 9.34 The Biology of Cancer (© Garland Science 2007)
Anti-apoptotic strategies used by cancer cells
Cancer cells res...
Figure 9.37 The Biology of Cancer (© Garland Science 2007)
The Apoptotic Circuit Board
The full array of components govern...
Cancer cells invent numerous ways to inactivate the
apoptotic machinery in order to survive
Among these are the activation...
BOC lecture 7 cell death
BOC lecture 7 cell death
BOC lecture 7 cell death
BOC lecture 7 cell death
BOC lecture 7 cell death
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BOC lecture 7 cell death

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Transcript of "BOC lecture 7 cell death"

  1. 1. The Biology of Cancer Chapter 9: p53 and Apoptosis: Master Guardian and Executioner Cell Death
  2. 2. Apoptosis Autophagy Necrosis Programmed cell death. Death cycle is programmed by the cell itself ‘Self-eating’ Catabolic process involving lysosomes. ‘Death’ caused by external factors like trauma or toxins. Not programmed. Cell Death
  3. 3. The term was originally used by Wyllie and his colleagues and is from the Greek meaning “dropping away” as the leaves from a tree. Apoptosis: Programmed Cell Death Cell Suicide The Face of Cell Death: Apoptosis
  4. 4. Active cell death • Specific gene expression • Specific intracellular signals • Requires energy and RNA and protein synthesis • Characteristic morphological features • DNA cleaved, chromatin condenses • Cells shrink • Formation of apoptotic body • Cleared by phagocytosis • No inflammation=no tissue damage Passive cell death • Physical or chemical trauma • Cells swell up • Membrane breaks down and cellular contents leak out • Nucleus disintegrates • Cell ghosts • Inflammatory=tissue damage Apoptosis Necrosis
  5. 5. Figure 9.18d The Biology of Cancer (© Garland Science 2007) An apoptotic cell showing fragmented Golgi bodies (green)
  6. 6. Autophagy
  7. 7. Srcf.ucam.org Autophagy: clearing out garbage
  8. 8. The Face of Cell Death: Apoptosis
  9. 9. Two Apoptotic Pathways: Extrinsic & Intrinsic
  10. 10. Two Pathways that Initiate Apoptosis Intrinsic/ Mitochondrial Apoptosis Regulated by Mitochondrial Cytochrome C release Extrinsic/ Death Receptor Apoptosis Activated by ligation of Death Receptors Fas, TNF alpha These pathways intersect at the effector caspases
  11. 11. Two Pathways that Initiate Apoptosis
  12. 12. Intrinsic Pathway Chemotherapy Irradiation
  13. 13. Figure 9.29 The Biology of Cancer (© Garland Science 2007) The Apoptotic Caspase Cascade: Apoptosome The Wheel of Death Pro-apoptotic signals open channels in the mitochondrial membrane to allow cytchrome c and Smac/Diablo molecules to be released. Cytochrome c molecules bind to Apaf1 to form the apoptosome. The apoptosome activates pro-caspase 9 to caspase 9 which in turn activate caspase 3. Caspase 3 activates in turn, a series of executioner caspases which cleave various death substrates whose cleavage creates the apoptotic cell phenotype.
  14. 14. Figure 9.28 The Biology of Cancer (© Garland Science 2007) The Wheel of Death - Apoptosome The apoptosome is assembled in the cytosol when cytochrome c molecules are released from the mitochondria into the cytosol.
  15. 15. The apoptosome associates with Apaf1. this causes the assembly of the 7 spoked wheel in which Apaf-1 forms the spokes and the cyt c forms the tips. Once assembled this attracts procaspase 9 into the hub of the wheel which converts procaspase 9 into active caspase 9. The resulting caspase 9 proceeds in turn to cleave and activate other caspase molecules thereby triggering the apoptotic cascade. Caspase 9 is activated
  16. 16. Caspase 9 activates the executioner caspases Active caspase 9
  17. 17. Executioner caspases : Caspase 3, 6 & 7 cleave DNA by activating DNAase APOPTOSIS
  18. 18. Executioner caspases : Caspase 3, 6 & 7 cleave DNA by activating DNAase APOPTOSIS Caspase 9 is activated Caspase 9 activates the executioner caspases Mitochondrial Cyt C release INTRINSIC APOPTOTIC PATHWAY
  19. 19. The Extrinsic Pathway: In the extrinsic pathway, signal molecules known as ligands, which are released by other cells, bind to transmembrane death receptors on the target cell to induce apoptosis. For example, the immune system’s natural killer cells possess the Fas ligand (FasL) on their surface. The binding of the FasL to Fas receptors (a death receptor) on the target cell will trigger multiple receptors to aggregate together on the surface of the target cell. The aggregation of these receptors recruits an adaptor protein known as Fas- associated death domain protein (FADD) on the cytoplasmic side of the receptors. FADD, in turn, recruits caspase-8, an initiator protein, to form the death-inducing signal complex (DISC). Through the recruitment of caspase-8 to DISC, caspase-8 will be activated and it is now able to directly activate caspase- 3, an effector protein, to initiate degradation of the cell. The extrinsic apoptotic pathway
  20. 20. The Extrinsic Apoptotic Pathway Disc (death inducing signal complex) TRADD : tumor necrosis factor death domain, FADD: Fas associated death domain. Cleaves DNA
  21. 21. Figure 9.19 The Biology of Cancer (© Garland Science 2007) Apoptosis of cells forming webs between future mouse toes. The dark dots are apoptotic cells.
  22. 22. Apoptotic humor !
  23. 23. p53 and Apoptosis
  24. 24. Figure 9.8 The Biology of Cancer (© Garland Science 2007) p53 - activating signals’s and p53 downstream effects A variety of cell physiologic stresses can cause a rapid increase in p53 levels which proceeds to induce a number of responses.
  25. 25. A cancer cell does not want to undergo apoptosis hence it initiates anti-apoptotic strategies
  26. 26. Figure 9.34 The Biology of Cancer (© Garland Science 2007) Anti-apoptotic strategies used by cancer cells Cancer cells resort to numerous strategies in order to decrease the likelihood of apoptosis. This diagram indicates that in various cancer cell types the levels or activity of important pro-apoptotic proteins are decreased (blue). Conversely, the levels or activity of certain anti-apoptotic proteins may be increased (red).
  27. 27. Figure 9.37 The Biology of Cancer (© Garland Science 2007) The Apoptotic Circuit Board The full array of components governing apoptosis is not known. An initial attempt at modeling the system is shown.
  28. 28. Cancer cells invent numerous ways to inactivate the apoptotic machinery in order to survive Among these are the activation of Akt pathway, inactivation of p53 and also inhibition of caspases Loss of apoptotic functions allows cancer cells to survive a variety of cell physiological stresses such as DNA damage
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