Apoptosis Flashcards

1
Q

Morphological features of apoptotic cells

A
  • cell shrinkage/condensation
  • cytoskeleton collapse
  • heterochromatisation of nucleus (darkening around nuclear envelope)
  • nuclear fragmentation
  • cell surface bulges (blebs, apoptotic bodies)
  • no inflammation
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2
Q

Differences between necrosis and apoptosis

A

little inflammatory response

specific genes involved in apoptosis

distinct biochemical pathways for apop

  • removes unwanted cells (forming digits, elimination of lymphocytes)
  • activates suicide programme as a response to damage
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3
Q

Example of when apoptosis is needed in the immune system

A

post infection neutrophils and other lymphocytes are in high concentration
- apoptosis helps bring back to normal level

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4
Q

What is an key biochemical feature that is needed for phagocytosis of apoptotic cells

A

plasma membrane has phosphatidyl serine (a negatively charges phospholipid) usually in the inner layer of the PM

When undergoing apoptosis:
- phosphatidyl serines migrate to outer layer of PM which signals phagocytic cells to ingest the apoptotic cell

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5
Q

What are caspases

A

proteases
- cleaves specific target sequences in proteins

synthesised as procaspases which can be activated into caspases by other caspases

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6
Q

What are the classes of caspases and what are their functions

A

initiator caspases (begin apoptosis)

  • 8 and 9
  • exist as inactive, soluble monomers (procaspases) on cytosol

executioner caspases (activated by initiator caspses)

  • 3, 6 and 7
  • exist as an inactive dimer where their active site is rearranged when cleaves to the active conformation
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7
Q

How is the cell killed in apoptosis

A

cleavage of key proteins by caspases

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8
Q

What are the 2 signalling pathways which lead to apoptosis

A
  1. extrinsic pathway
    - caspases activated by the binding of apoptotic signals to death receptors
  2. intrinsic pathway
    - caspases activated from within the cell
    - used when DNA is damaged or there is a lack of oxygen
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9
Q

what is the Fas death receptor

A

tumour necrosis factor (TNF) receptor family

  • transmembrane homotrimer protein
  • CD95 best known type

Structure:

  • extracellular ligand binding domain
  • intracellular death domain
  • ligands are also homotrimers
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10
Q

What responses is CD95 death receptor involved in?

A
  • deletion of activated T cells at the end of immune response
  • killing of virus-infected and cancer cells by T cells
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11
Q

Fas receptor pathway of apoptosis

A
  1. killer lymphocytes produce a Fas ligand which binds to the extracellular death receptor
  2. Fas receptor recruits intracellular adaptor proteins which bind to the death domain
  3. procaspse 8 binds to the death effector domain on the adaptor protein
  4. caspase 8 becomes activated and then activates other executioner caspases
  5. apoptosis is induced
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12
Q

Intrinsic pathway (full process)

A
  1. cytochrome c is released from mitochondria into cytosol
  2. cytochrome c activates Apaf-1 (apoptotic protease activating factor 1) which forms an apoptosome
    • many of the Apaf-1 and cytochrome c molecules forms a spinning
      wheel via CARD domains which allows the addition of procaspase
      9 to bind via CARD domains
  3. apoptosome binds to and activates pro-caspase 9
  4. caspase 9 activation leads to activation of exectutioner caspases
  5. cleavage of cellular proteins which induces apoptosis
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13
Q

Which proteins help regulate the intrinsic pathway

A

Bcl2 proteins

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14
Q

What are Bcl2 proteins

A

conserved proteins

2 functional classes:

  • pro-apoptotic (induces apoptosis)
  • anti-apoptotic (stops apoptosis)

these proteins can bind to each. other forming heterodimer combinations which influence the release of cytochrome c

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15
Q

What are the classes distinct BH domains of Bcl2 proteins

A
  1. anti apoptotic
    • BH1-4
    • e.g. Bcl2, Bcl-XL
  2. pro-apoptotic BH123
    • e.g Bax, Bak
  3. pro-apoptotic BH3 only
    • e.g Bad, Bim, Bid, Puma, Nova
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16
Q

When the intrinsic pathway is inactive how do the Bcl2 proteins interact

A

Bax and Bak (effector Bcl2 proteins) found in mitochondrial membrane but inactive as anti-apoptotic Bcl2 inhibits effector Bcl2 proteins

Stopping the release of cytochrome c

17
Q

When the intrinsic pathway is active how to Bcl2 proteins interact?

A
  1. apoptotic stimulus activates BH3 only Bcl2 effector proteins (Puma, Noxa)
  2. activated BH3 only inactivates anti-apoptotic Bcl2 proteins
  3. this allows effector Bcl2 proteins (Bax and Bak) on the mitochondrial membrane to bind together forming a heterodimer channel allowing cytochrome c to be released
18
Q

How can the extrinsic and intrinsic apoptotic pathways be linked?

A
  1. activated caspase 8 from the extrinsic pathway can cleave Bid (BH3 only protein)
  2. This activates Bid which can then inactivate anti-apoptotic Bcl2 protein blocking bax and bak in the mitochondrial membrane
19
Q

what is the function of Inhibitors of Apoptosis (IAP’s) and how do they do this

A

XIAP

ensures apoptosis is not accidentally triggered by binding and inhibiting activated caspases

  • some ubiquitinate caspases for proteasome digestion
20
Q

How are IAP’s stopped when apoptosis does need to occur and examples of them

A

anti-IAP’s which block IAP’s to promote apoptosis

examples:
- Smac/Diablo (released with cytochrome c from mitochondria

21
Q

What is Syndactyly

A

incomplete separation of digits due to lack of apoptosis during embryonic development