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BMR 603 Test 2 > Apoptosis > Flashcards

Apoptosis Flashcards

1
Q

What is apoptosis?

A
  • programmed cell death – cells go through sequence of changes leading to death and engulfment
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2
Q

What is necrosis?

A

cells burst, releasing intracellular contents

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3
Q

Is apoptosis irreversible once started?

A

Yes

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4
Q

Apoptosis process (5 steps)

A
  • Chromosomal DNA begins to fragment due to cleavage by nucleosomes
  • Chromatin condenses and nucleus breaks up into small pieces
  • Cytoskeleton breaks up
  • Cell shrinks and breaks up into membrane-enclosed fragments
    • Known as blebbing
  • Apoptotic cell is recognized and phagocytized by macrophages.
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5
Q

What is the signal for phagocytization in apoptotic cells?

A
  • Phosphatidylserine translocated from inner leaflet to outer leaflet of plasma membrane.
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6
Q

Function of Caspases?

A
  • They are cysteine proteases that cleave after aspartate residues
  • Normally present as inactive precursors.
    • Activated by cleavage by other caspases
  • Cleave proteins at only a few residues
  • Initiators and executioners.
  • Examples of Cleaved:
    • Inhibitor of Dnase that cleaves genomic DNA between nucleosomes
    • Nuclear lamins
    • Cytoskeletal proteins
    • Inhibitors of apoptosis
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7
Q

What 4 genes play a role in apoptosis in C. elegans?

A
  • Required for apoptosis to occur:
    • ced-3
    • ced-4
    • egl-1
  • Negative regulator of apoptosis
    • ced-9
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8
Q

Apoptotic pathway of C. elegans?

A
  • ced-9 binds to ced-4, preventing it from activating ced-3
  • When ced-9 is removed by egl-1, ced-4 now able to bind to ced-3
  • ced-3 cleaves itself to form active caspase
  • ced-3 now cleave proteins in cell destined to die.
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9
Q

Role of ced-3?

A

Cleaves itself to form active caspase then cleaves proteins in cell destined to die.

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10
Q

Role of ced-4?

A

Activates ced-3

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11
Q

Role of egl-1?

A

Removes ced-9 from ced-4.

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12
Q

Role of ced-9?

A

Binds to ced-4, thus preventing the activation of ced-3 and starting apoptosis.

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13
Q

What family of proteins determines if apoptosis occurs in invertebrates?

A
  • Bcl-2 family of proteins
    • Play the role of both activators and inhibitors of apoptosis.
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14
Q

What are the two pathways of vertebrate apoptosis?

A

Intrinsic/stress

Extrinsic/death receptors

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15
Q

Bcl-2 family proteins:

Name three members that activate apoptosis and how they do so.

A
  • Bad, Bax, Bid
  • Activate apoptosis by translocating to mitochondria, where they are thought to disrupt integrity allowing cytochrome C to release.
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16
Q

Bcl-2 family proteins:

Name three members that activate apoptosis and how they do so.

A
  • Bcl-2, Bcl-xL, Bcl-w
  • Inhibit apoptosis by sequestering pro-apoptotic proteins.
17
Q

Function of Bcl-2 proteins with 1 BH3 domain

A
  • Pro-apoptotic
  • Bid, Bad, Bim, Noxa, Puma
  • Have both activator and enabler/derepressor activities
    • Activated by multiple stimuli to initiate apoptosis
18
Q

Function of Bcl-2 proteins with 3 BH3 domains

A
  • Pro-apoptotic
  • Bax, Bak
19
Q

Function of Bcl-2 proteins with 4 BH3 domains

A
  • Anti-apoptotic
  • Bcl-2, Bcl-w, Bcl-xL
20
Q

Mitochondrial pathway for apoptosis?

A
  • Predominantly release of proteins that trigger activation of apoptosis
    • Could also involve disruption of Electron transport or reactive oxygen species
  • Formation of apoptosome
    • Damage to DNA or mitochondria occurs
      • Apaf-1 and cytochrome c complex with caspase-9 and ATP/dATP in cytoplasm
        • (Apoptosome)
    • Apaf-1 ans caspase-9 interact through N-terminal CARDs
    • Caspase-9 is activated by autocleavage
    • activates downstream caspases
21
Q

Mitochondrial Apoptosis

Downstream caspases?

A
  • Directly Activated:
    • Caspase 3
  • Indirectly activated:
    • Caspases -2,-6,-8,-10
22
Q

How is caspase-9 activated?

A

Autocleavage

23
Q

Components of apoptosome?

A

Apaf-1, cytochrome c, caspase-9 and ATP/dATP

24
Q

Death receptor pathway?

A

In immune system, Fas receptor controls apoptosis

Ligand for Fas is FasL, a trimer of indentical polypeptides.

25
Q

Fas/FasL pathway mechanism

A
  • Membrane-bound FasL binds to Fas on adjacent cell
    • Induces trimerization of Fas
  • Trimerized Fas binds to adaptor (FADD protein) via death domains at C-termini of both proteins
  • TRADD - required by some death receptors but not all
  • FADD binds to inactive caspase-8
    • Complex becomes “death-inducing signaling complex” (DISC)
  • Autocleavage of caspase-8
    • Caspase-8 translocates from cytoplasmic tail of Fas-FADD complex to cytoplasm
    • Activates downstream caspases
      • Like, caspase-1
    • Also cleaves Bid, Bcl2 protein that then disrupts the mitochondria.
26
Q

Comparison of apoptotic pathways

A
  • C. elegans
    • Egl-1 inhibits CED-9, which was inhibiting CED-4, CED-4 now activates CED-3. CED-3 induces apoptosis.
  • Mammals
    • Bcl-2 pathway
      • Bik and Bax inhibit Bcl-2 which was inhibiting Apaf-1.
      • Apaf-1 now activates caspase-9 and thus apoptosis
    • Fas/CD95 pathway
      • CD95 activates FADD which activates Caspase-8 leading to apoptosis.
27
Q

Where does FADD bind to Caspase-8

A

FADD has a death effector domain (DED) at it’s N-terminus. It binds inactive caspase-8 here to activate it.

28
Q

Two pathways of inhibiting apoptosis

A

PI3-kinase pathway

PKB pathway

29
Q

Describe PI3-Kinase pathway

A
  • Activated by tyrosine kinases or G-protein
  • PI3-kinase phosphorylates PIP2 to form PIP3
    • PIP3 recruits Akt, serine-threonine kinase, to the plasma membrane
  • Akt is phosphrylated by PDK
  • Active Akt phosphorylates proteins: Bad and Caspase-9 which regulate apoptosis.
    • Bad when phosphorylated binds to 14-3-3 which inactivate it in the cytosol.
30
Q

Describe the PKB pathway?

A
  • Survival factor binds to receptor
  • Activates protein kinase B
  • PKB phosphorylates and inactivates Bad
  • Also, phosphorylates and inactivates regulatory proteins that stimulate transcription of apoptosis promoting proteins.
31
Q

Positive feedback and amplification loops in apoptosis regulation?

A
  • Caspases activate downstream caspases
  • Cleave anti-apoptotic proteins
    • Fragments then promote apoptosis.
32
Q

Regulation of apoptosis by buffers/dampeners?

A
  • Bcl-2 family of anit-apoptotic proteins
  • Inhibitors of apoptosis proteins (IAPs)
    • Bind to procaspases to prevent activation
    • Bind to caspases and either inhibit activation or cause ubiquitination
  • FLIPs
    • Similar to caspase-8 but lacks catalytic residues
    • Competes with caspase-8 for binding to FADD
  • Decoy receptors
    • Bind to apoptosis-inducing ligand, but cannot transduce apoptotic signal.
33
Q

What proteins inhibit IAPs?

A

Smac/DIABLO and Omni

Sequesters IAP in mitrochondrial intermembrane space.

BMR 603 Test 2 (9 decks)

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