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eMCD - Can > Cancer 10: Apoptosis > Flashcards

Cancer 10: Apoptosis Flashcards

1
Q

What are the 4 main functions of apoptosis ?

A
  1. Harmful cells
  2. developmentally defective cells
  3. remove excess / unnecessary cells
  4. obsolete cells (e.g maxillary epithelium at end of lactation)
  5. exploitation (e.g chemotherapy)
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2
Q

what is the difference btw necrosis vs apoptosis

A

necrosis = unregulated cell death associated with trauma, cellular disruption and an inflammatory response

Apoptosis = regulated cell death; controlled disassembly of cellular contents without disruption; no inflammatory response

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3
Q

What happens in necrosis?

A
  • Plasma membrane becomes permeable
  • Cells swell and cellular membrane ruptures
  • Chromatin condense
  • Release of proteases leading to autodigestion and dissolution of the cell
  • cells lyse
  • Localised inflammation occurs
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4
Q

What are the 2 phases of apoptosis?

A
  • latent phase

- execution phase

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5
Q

What happens in the latent phase of apoptosis?

A
  • death pathways are activated,

but cells= morphologically the same

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6
Q

What happens in the execution phase of apoptosis?

A
  • Loss of microvilli and intercellular junctions
  • Cell shrinkage –> then epithelium closes around
  • Loss of plasma membrane asymmetry (phosphatidylserine lipid appears in outer leaflet)
  • Chromatin and nuclear condensation
  • DNA fragmentation occurs
  • Formation of membrane blebs
  • Fragmentation of membrane-enclosed apoptotic bodies
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7
Q

Is there inflammation involved in apoptosis?

A

no

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8
Q

What happens to the apoptic body ?

A
  • it is phagocytosised by surrounding cells

e. g macrophages

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9
Q

how can DNA modification help detect apoptosis?

a) DNA LADDERS
you can detect apoptosis by DNA degradation –> (DNA fragmentation)
- separate DNA by size

at first: DNA = too big cant move don’t down gel
- later: DNA ladder fragments visible

b) TUNEL assay

A

-

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10
Q

What are 2 Other types of cell death (except necrosis + apoptosis)

A

(PCD = programmed) - shows spectrum/graded response

  • Apoptosis-like PCD = shows some, but not all, features of apoptosis. Display of phagocytic recognition molecules before plasma membrane lysis
  • Necrosis-like PCD = shows variable features of apoptosis before cell lysis; “Aborted apoptosis”
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11
Q

What are 4 mechanisms of apoptotic cell death?

A
  1. The executioners – Caspases
  2. Initiating the death programme
    - via Death receptors OR Mitochondria
  3. The Bcl-2 family
  4. Stopping the death programme
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12
Q

What are caspases (in apoptosis) ?

what are the 2 types of caspases?

A

caspases

  • -> triggers apoptosis
  • -> activated by proteolysis
  • -> initiates cascade of activation

there are 2 types of caspases:
a) Initiator caspases – first triggered (2, 9, 10, 8)
has 2 domains:
–> CARD = (CAspase Recruitment Domain) localises caspases at specific sites in cell
–> DED (Death Effector Domain) specific for caspases 8/10

CARD + DED ==> targeting subunits - protein-protein interactions (adapters), provide scaffolding

b) Effector caspases = 3, 6, 7 (P20/10 motifs)

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13
Q

Describe the maturation of the Caspase

A
  • They are made as zymogens (pro-caspases) - inactive
  • -> proteolytic cleavage of 2 procaspases to remove respective pro-domains releases the long + short subunits
  • Next, folding of 2 large + 2 small chains –> forms active L2S2 hetero-tetramer
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14
Q

Describe the caspase cascades

A

caspase cascades

  • allows amplification,
  • allows divergent responses
  • allows regulation

– caspase 8 + 9 –> initiator caspases that trigger apoptosis by cleaving and activating

  • others = effector caspases
    carry out apoptotic programme
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15
Q

How do effector caspases execute the apoptotic programme?

2 methods

A

a) they cleave and inactivate proteins or complexes -that would normally stop apoptosis (e.g lamin cleavages –> nuclear breakdown)

b) They activate enzymes by direct cleavage, or
cleavage of inhibitory molecules

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16
Q

What are the 2 mechanisms of caspase activation?

A
  1. Death by design
    – Receptor-mediated (extrinsic) pathways
    - ligand binds to death receptors –> which activates the death domain in the cytoplasmic domain of the receptor –> DED of procaspase binds to DD –> forms (DISC) –> activates procaspase –> activation
  • Receptors have Transmemb, cysteine-rich extracellular domains
  • Intracellular death domains –> attract adapter proteins

FADD = activating adaptor proteins
FLIP = inhibitory adaptor proteins
–> tightly controlled

Death by default – Mitochondrial (intrinsic) death pathway:
- exposure to cellular stress

- Loss of mitochondrial
membrane potential (ΔΨ)
  • Release of cytochrome c
  • Release of other apoptosis-
    inducing factors
- Formation of the
apoptosome complex (Caspase 9, Apaf1)
17
Q

What are the 3 ways of signalling through death receptors ?

e.g Fas/Fas-Ligand

A
  1. Receptor (Fas) trimerisation by ligand (Fas-L on lymphocyte)
  2. Recruitment of adapter protein (FADD) through its DD to DD of Fas
  3. Recruitment and oligomerisation of procaspase 8 through its DED to FADD DED –> Death-Inducing Signalling Complex (DISC)

–>

18
Q

How does initiator procapsase 8 oligomerisation results in cleavage and activation ?

A
  • Procaspase 8 interacts with DED –> cleaves procaspase –> active tetramer released
  • Some initiator procaspases have (some) intrinsic low catalytic activity – oligomerisation allows transcleavage
  • Other caspases = activated by conformational change on oligomerisation
  • Need at least 2 procaspases to form active tetramer
19
Q

How does FLIP inhibit procaspase 8 activation?

A
  • FLIP competes for binding to receptor tails / FADD via DED domains

–> and Incorporates into receptor-procaspase complexes and interferes with transcleavage

–> because it cant form tetramer

20
Q

CARD = docking site for bringing lots of caspases together

A

-

21
Q

Apoptosis requires / doesn’t require energy

Necrosis requires / doesn’t require energy

A

apoptosome requires ATP

Necrosis doesn’t require energy

22
Q

Principal mechanisms of apoptosis: Bid links receptor and mitochondrial death pathways

A

apoptosome feeds into caspase 3 –> causes proteolysis and cell death

caspar 8 can cleave protein BID –> promotes and inhales proteolysis ad cell death
(requires ATP)

23
Q

What are the main modulators of apoptosis?

A
  • Anti-apoptotic proteins = Bcl-2 and Bcl-xL, (hooked on mitochondria)
  • Pro-apoptotic proteins = Bid, Bad, Bax, Bak (move between Cytosol and Mitochondria)
24
Q

How is PI3’-Kinase signalling pathway involved in growth + cell survival?

A

o PIP3 activates protein kinase PKB/Akt which is anti-apoptotic + Phosphate-dependent kinase (PDK) –> induces cell survival

  • -> PKB/Akt acts by:
    1. Phosphorylates and inactivates Bad
  1. Phosphorylates and inactivates caspase 9
  2. Inactivates FOXO transcription factors (FOXOs promote expression of apoptosis-promoting genes)
  3. Other, e.g. stimulates ribosome production and protein synthesis
25
Q

Describe the Regulation of apoptosis by Bcl-2 proteins via BH3 heterodimerisation:

A

Bcl-xL/2 localised on mitochondria + form inactive dimers w/ other Bcl-2 family

  • In cytosol, have inactive phosphorylated Bad
  • If remove GFs, Bad dephosphorylated –> released from docking proteins + becomes active –> moves to mitochondria –> displace Bcl-2/xL
  • Bax/bak form pore in mitochondrial membrane –> release cytochrome C –> pro-apoptotic
26
Q

PTEN (lipid phosphatase) counteracts PI3’-K signalling

A

????

27
Q

how does inhibitor of Apoptosis Proteins (IAPs) regulate Programmed cell death?

A

Extrinsic pathway

  • they Bind to procaspases –> prevent activation
  • can also Bind to active caspases –> inhibit activity
28
Q
  • Bcl-2, Bcl-xL regulate intrinsic /extrinsic pathway
  • FLIP, IAPs regulate intrinsic / extrinsic pathway
  • GF pathways via PI3’-K and PKB/Akt –> promote cell survival / death
A
  • Bcl-2, Bcl-xL regulate intrinsic pathway
  • FLIP, IAPs regulate extrinsic pathway
  • GF pathways via PI3’-K and PKB/Akt –> promote cell survival
29
Q

What are some therapeutic uses of programmed cell death?

A

Harmful (oncogenic) cells (e.g. cells with viral infection, DNA damage)

Chemotherapeutic killing of tumour cells, e.g. Dexamethasone stimulates DNA cleavage

30
Q

how many apaf 1 monomers join the apoptosome?

a) how is the monomer become an apoptosome?

A

7

a) monomoer –> signal – heptomer –> recruit caspases –>form apoptosome

31
Q

apoptosome requires/ doesn’t require ATP

A

apoptosome requires ATP

32
Q

note: BH3 = allows dimerisation of the motifs

A

-

eMCD - Can (15 decks)

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