Apoptosis Flashcards

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1
Q

Is apoptosis or necrosis the most common form of cell death?

A

Apoptosis

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2
Q

True or False:

In apoptosis, cell contents spill out; in necrosis, cells shrink and condense.

A

False - apoptosis, cells shrink and condense (contents never leak out); necrosis, cell contents spill out.

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3
Q

Give an example of apoptosis being important in development of mice and humans.

A

Apoptosis (cell death) sculpts hands and feet during embryonic development. Thus, keeping hands and feet from being webbed.

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4
Q

List the phenotype of apoptosis (characteristics).

A
  • overall shrinkage in volume of cell and its nucleus.
  • loss of adhesion to neighboring cells.
  • formation of bless on surface.
  • DNA fragmentation
  • cytoskeleton collapses
  • nuclear envelope disassembles.
  • rapid engulfment of dying cell by phagocytosis (macrophages).
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5
Q

What type of certain cells is programmed cell death important for?

A
  • abnormal cells
  • non-functional cells
  • potentially dangerous cells
  • eliminating lymphocytes after destroying and ingesting microbes
  • keep organs the correct size (liver)
  • DNA damaged cells are destroyed if bad enough damage
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6
Q

When running an agarose gel to look at the characteristics of apoptotic cells, where does the endonuclease the DNA resulting in a ladder of fragments in distinctive sizes?

A

Endonuclease cleaves in linker regions of nucleosomes.

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7
Q

What is the key event to initiate apoptosis?

A

Activation of caspases.

Caspase = Cysteine Aspartyl specific proteASE

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8
Q

What amino acid is the active site in caspases?

A

Cysteine in active site.

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9
Q

Where does caspase cleave target proteins?

A

Caspase targets proteins and cleaves them in their sequence where an aspartic amino acid residue occurs.

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10
Q

What inactive precursor is caspases synthesized first as?

A

Procaspase

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11
Q

To activate procaspase, what is it cleaved to form?

A

Procaspases cleaved at specific sites to form a large and small subunit which form a heterodimer - caspases activates procaspase.

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12
Q

What are the two major classes of caspases?

A
  • Initiator caspase

- executioner caspase

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13
Q

What do initiator caspases do?

A

Initiate apoptosis (including caspase-8 and caspase-9)

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14
Q

What do executioner caspases do?

A

Destroys actual targets - executes apoptosis (includes caspase-3).

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15
Q

True or False:

The caspase cascade is irreversible.

A

True

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16
Q

What do activated caspases do?

A
  • cleaves downstream proteins
  • cleaves inactive endonuclease
  • targets cytoskeleton
  • attacks cells adhesion proteins (cells roll up in ball)
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17
Q

True or False:

Executioner caspases auto-activates itself.

A

False - Initiator caspase auto-activates itself.

executioner caspases cleaves cellular targets

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18
Q

What are the two apoptotic pathways?

A
  • internal pathway

- external pathway

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19
Q

Give an example of an internal stimuli that activates the internal apoptotic pathway.

A

Abnormalities in DNA.

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20
Q

Give an example of an external stimuli that activates the external apoptotic pathway.

A

Removal of survival factors and proteins of tumor necrosis factor family.

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21
Q

Is the internal apoptotic pathway or external apoptotic pathway mitochondrial dependent?

A
  • Intrinsic pathway is mitochondrial dependent.

- Extrinsic pathway is mitochondrial independent.

22
Q

What are the 3 domains that compose death receptors in the extrinsic apoptotic pathway?

A
  • extracellular binding domain
  • single transmembrane domain
  • intracellular death domain
23
Q

What is apoptosis?

A

A routine controlled cell death that minimizes spread of damage and/or inflammation.

Is cell death under physiological conditions.

Clean way of dying.

Apoptosis is programmed cell death.

Apoptosis is an intracellular proteolytic cascade mediated by proteases called caspases.

24
Q

True or False:

To initiate the extrinsic apoptosis pathway, extracellular signals bind to cell surface death receptors and trigger the extrinsic pathway.

A

True

25
Q

Are the death receptors of the extrinsic pathway homotrimers or heterotrimers?

A

homotrimers - 3 proteins of same type (members of TNF family of proteins)

26
Q

In the apoptosis extrinsic pathway, what ligand binds to Fas death receptors?

A

Fas

27
Q

Once Fas binds to Fas death receptors in he extrinsic apoptosis pathway, what adaptor proteins are recruited?

A
  • FADD adaptor (Fas associated death domain)

- Procaspase-8 with death effector domain

28
Q

What forms the DISC complex in the extrinsic apoptosis pathway?

A
  • FADD adaptor protein (binds to Fas death receptor)

- Procaspase-8 or 10 (binds to death effector domain, which is a FADD adaptor domain)

29
Q

In the extrinsic apoptosis pathway, what does activated caspase-8 or 10 activate?

A

Executioner caspases (e.g., caspase-3)

30
Q

What is the role of decoy receptors in the extrinsic apoptosis pathway?

A
  • Decoy receptors have ligand binding domain but no death domain.
    > bind death ligand but does not activate apoptosis
    > thus, they are inhibitory proteins that restrain the extrinsic pathway
31
Q

In the extrinsic apoptosis pathway, what is the function of FLIP proteins?

A
  • is a competitive inhibitor against procaspase-8 and procaspase-10 = prevents apoptosis.
  • FLIP is a protein resembling initiator procaspase with NO proteolytic domain.
32
Q

List some reasons that a cell would activate apoptosis from inside of the cell via the intrinsic pathway.

A
  • in response to injury
  • DNA damage and lack of oxygen
  • nutrients
  • extracellular survival signals
33
Q

What is the key event of the intrinsic apoptosis pathway?

A

The translocation of cytochrome C from the intermediate space of mitochondria is the key event.

34
Q

In the intrinsic apoptosis pathway, where is cytochrome c released from and what is its function?

A
  • cytochrome c is translocated from intermediate space of mitochondria into the cytosol.
  • cytochrome c binds to procaspase-activating adaptor protein Apaf1 (apoptotic protease activating factor-1).
  • Apaf1 forms apoptosome which activates caspase-9.
  • Caspase-9 activates downstream executioner caspases (caspase-3, which is common to both pathways).
35
Q

What triggers the assembly of the apoptosome?

A

Release of dADP in exchange for dATP (or ATP).

36
Q

What happens during the event of cytochrome c activation of Apaf1?

A

Activation of Apaf1 by cytochrome c and hydrolysis of bound dATP to dADP.

Remember: The assembly of apoptosome is then triggered by the releases of the dADP in exchange for dATP (or ATP).

37
Q

What protein regulates the intrinsic apoptotic pathway by controlling the release of cytochrome c into the cytosol from the intermediate space of the mitochondria?

A

Bcl2

(Bcl = B Cell Lymphoma)

38
Q

What are the two different types of Bcl2 proteins that regulate the intrinsic apoptotic pathway?

A
  • Pro-apoptotic

- Anti-apoptotic (pro-survival)

39
Q

What does the pro-apoptotic Bcl2 protein function to do in the intrinsic apoptotic pathway?

A

Promotes release of cytochrome c.

40
Q

What does the anti-apoptotic Bcl2 protein function to do in the intrinsic apoptotic pathway?

A

Blocks the release of cytochrome c.

41
Q

What are the distinctive domains of anti-apoptotic protein Bcl2?

A

Has 4 distinctive domains - called Bcl homology domains or BH domains.

42
Q

What are the domains of pro-apoptotic protein Bcl2 in the intrinsic apoptotic pathway?

A

BH123 protein + BH-3 only protein.

43
Q

What are the 3 classes of Bcl2 proteins?

A
> Anti-apoptotic Bcl2 protein (BH1234)
     - e.g., Bcl2, Bcl-XL
> Pro-apoptotic BH123 protein
     - e.g., Bax, Bak 
> Pro-apoptotic BH3- only protein 
     - e.g., Bad, Bim, Bid, Puma, Noxa
44
Q

What is the mechanism of BH123 protein in apoptosis?

A
  • apoptotic stimulus triggers intrinsic pathway
  • BH123 proteins become activated
  • from aggregation in mitochondrial outer membrane and induce release of cytochrome c
  • then apoptosome formed by binding to Apaf1
45
Q

Where are anti-apoptotic Bcl proteins, like Bcl2 and Bcl-XL, mainly located?

A

Cytosolic surface of outer mitochondrial membrane.

46
Q

What do anti-apoptotic Bcl proteins, like Bcl2 and Bcl-XL, function to do?

A

These proteins prevent apoptosis by binding to pro-apoptotic proteins (e.g., BH123) and prevent aggregation into active form.

47
Q

What happens when BH3- only protein (pro-apoptotic) is activated?

A

Activated BH3-only protein is cytosolic and translocates to mitochondria after apoptotic signal activates it (pro-apoptotic).

It inhibits anti-apoptotic Bcl2 protein from inhibiting aggregation to release cytochrome c.

48
Q

What do IAP proteins function to do in the regulation of apoptosis?

A
  • IAPs = Inhibitors of Apoptosis
  • bind and inhibit caspases
  • some IAPs add ubiquitin to caspases to mark them for destruction by proteasome
  • IAPs block apoptosis by binding to caspases
49
Q

What is the role of anti-IAPs in the regulation of apoptosis?

A

If there is apoptotic stimuli or apoptosis signals…….then this causes release of anti-IAPs from mitochondria to block activity of IAPs.

Executioner caspases can therefore be activated with the IAPs blocked.

anti-IAPs neutralize the IAPs and liberate the caspases

50
Q

Insufficient apoptosis can contribute to disease.

A

> Due to chromosome translocation that causes excessive Bcl2 to be made - Bcl2 is inhibitor of apoptosis.
Excess Bcl2 promotes development of cancer by inhibiting apoptosis - DNA-damaged cells will not be programmed for cell death but can go on to cause cancer.

> p53 mutation:

  • mutated p53 can no longer cause cell cycle arrest
  • and no longer promotes apoptosis
  • cells with DNA damage stick around and cancer can be generated

excessive apoptosis can be a problem too - this occurs in heart attacks and strokes