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Year 2 Collin > Cancer 9 - Apoptosis > Flashcards

Cancer 9 - Apoptosis Flashcards

1
Q

Why do cells undergo apoptosis (programmed cell death - PCD)

A
  1. Harmful cells
  2. Developmentally defective cells
  3. Excess/unnecessary cells
  4. Obsolete cells
  5. Exploitation
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2
Q

What are the differences between necrosis and apoptosis

A

Necrosis = unregulated cell death, associated with trauma, cellular disruption and INFLAMMATORY RESPONSE

Apoptosis = regulated cell death, controlled disassembly of cellular contents without disruption, NO INFLAMMATORY RESPONSE

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3
Q

Explain how necrosis happens (localised inflammation)

A
  1. Plasma membrane becomes permeable (e.g. trauma)
  2. Chromatin condenses, fluid rushes in –> cell swells and cellular membrane ruptures
  3. Release of proteases –> autodigestion and dissolution of cell
  4. Cell lysis, invasion of phagocytic cells, inflammation
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4
Q

What are the 2 phases of apoptosis and what happens in each phase

A
  1. Latent phase - death pathways activated but cell remains morphologically the same
  2. Execution phase - Loss of microvilli and intercellular junctions
    - cell shrinkage
    - loss of plasma membrane asymmetry (phosphatydylserine appears in outer leaflet/membrane)
    - Chromatin and nuclear condensation
    - DNA fragmentation
    - Formation of membrane blebs
    - fragments enclosed into membrane enclosed apoptotic bodies
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5
Q

Apoptotic bodies are phagocytosed by….?

A

Macrophages

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6
Q

Why is there no inflammation in apoptosis?

A

Because the cellular contents is not released so no mediators are attracted

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7
Q

As the cell shrinks in apoptosis, what closes around it? Why

A

Epithelium closes around it to prevent entry of things such as pathogens via the lumen

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8
Q

How can apoptotic nuclei be detected

A
  1. DNA ladders - show fragmentation as DNA is being broken down
  2. Adding fluorescent tagged base - DNA fragmentation = more ends = brighter nuclei show more fragmentation
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9
Q

Aside from necrosis and apoptosis, what are the other forms of cell death

This is a graded response

A
  1. Apoptosis-like PCD = has some but not all features of apoptosis - phagocytic recognition molecules displayed before plasma lysis
  2. Necrosis-like PCD - variable features of apoptosis before cell lysis - “aborted apoptosis”
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10
Q

What do caspases (Cysteine-dependent Aspartate-directed Proteases) do?

A

They degrade everything inside the cell - “the executioner”

They are activated by proteolysis - trigger cascade of activation

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11
Q

What are the 2 types of caspases

A
  1. Initiator caspases - these are triggered first.
    2 domains:

CARD (Caspase Recruitment Domain) (cascades 2, 9)

DED (Death Effector Domain) (cascades 10, 8) - these have homotypic protein-protein interactions, provide scaffolding

  1. Effector caspases - these do the chopping up (caspases 3,6,7)
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12
Q

How does caspase maturation happen

A

Zymogens (procaspases) undergo proteolytic cleavage –> removes the pro-domains and it separates to form 2 distinct long (L) and short (S) subunits –> which then forms an active L2S2 hetero-tetramer

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13
Q

Which 3 things do caspase cascades involve

A
  1. Amplification
  2. Divergent responses
  3. Regulation
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14
Q

How do initiator cascades trigger apoptosis?

A

By cleaving and activating effector caspases (which carry out the apoptotic programme)

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15
Q

What 4 actions can effector caspases have

A

(Monomeric substrates)

  1. Inactivation
  2. Activation

(Multiprotein complexes)

  1. Disassembly
  2. Release
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16
Q

Give an example of a nuclease that is activated by effector caspases

A

Caspase-Activated-DNase (CAD)

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17
Q

Give an example of a protein/complex being cleaved and inactivated by effector caspases

A

Nuclear lamins cleaved - leading to nuclear breakdown

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18
Q

What are the 2 mechanisms of caspase activation

A
  1. Death by design - receptor mediated (extrinsic) pathways

2. Death by default - mitochondrial (intrinsic) pathway

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19
Q

Describe death receptors

A
  1. They are transmembrane, cysteine-rich extracellular domains that are trimerised
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20
Q

What do intracellular death domains attract

A

Adapter proteins

21
Q

Name and describe the roles of 2 adapter proteins in receptor-mediated apoptosis

A
  1. FADD - has a DED and DD domain - responsible for activating apoptotic path
  2. FLIP - 2x DED domain - inhibits apoptotic path

DD and DED domains bind to similar domains on other proteins

22
Q

Explain how signalling via death receptors occurs in the Fas/L

A
  1. Fas receptor trimerised - due to FasL on lymphocyte
  2. FADD (adapter protein) recruited via its DD to the DD of Fas
  3. Recruitment and oligomerisation of procaspase 8 (via its DED to FADD DED) —> triggers DISC (Death-Inducing Signalling Complex)
23
Q

How many procaspases are needed to form an active tetramer

A

2

24
Q

Which 2 ways can activate procaspase 8

A
  1. Transcleavage
  2. Conformational change upon oligomerisation

(active procaspase is released when procaspase 8 interacts with DED which causes cleavage)

25
Q

What are the two types of FLIP?

A

Small and long FLIP - they have the same homology in the DED domain as the procaspases but they have no proteolytic activity - so the FLIPs must compete with the procaspase to inhibit activation of caspase 8

Essentially FLIP inhibits procaspase 8 activity by binding onto the DED domain of the Fas/FADD receptor tail - no proteolytic compartment so no transcleavage

26
Q

Describe the intrinsic pathway of apoptosis (mitochondrial regulation)

A
  1. Loss of mitochondrial membrane potential due to cellular stress
  2. Release of Cytochrome C and other apoptosis inducing factors into cytoplasm
  3. Formation of the apoptosome complex
27
Q

What are the constituents of the apoptosome complex

A

Apoptotic activating factor-1 (APAF-1), procaspase 9, ATP, Cytochrome C

28
Q

Describe the role(s) of Apaf-1 in the apoptosome

Apaf-1 is a scaffolding protein to organise the apoptosome

A
  1. Has CARD domains at the centre of the wheel to recruit caspases
  2. Has WD-40 repeats at C terminal - which binds to cytochrome c
29
Q

When stimulated, the apoptosome is a ……..meric structure

A

Heptameric

30
Q

How are the caspases involved in the apoptosome

A

Procaspase 9 binds (docks) onto the CARD, and forms a dimer with caspase 9 in the middle of the wheel - potentially 7 procaspase 9s can bind as well (heptameric)

Oligomerization brings many procaspase 9s together - which results in cleavage and activation –> release of active caspase 9 tetramer –> initiating the caspase cascade —> which triggers apoptosis

31
Q

What is an essential requirement for the apoptosome

A

ATP

32
Q

What may determine whether cell death is by necrosis or apoptosis

A

Energy levels in the cell

33
Q

How may the extrinsic and intrinsic apoptotic pathway be linked

A

The extrinsic pathway, upon activation of caspase 8, activates Bid proteins which stimulates the intrinsic (mitochondrial) pathway by stimulating release of mitochondrial proteins into cytoplasm.

Caspase 8 and apoptosome then go onto activate caspase 3

34
Q

Which family of proteins modulates apoptosis?

A

Bcl-2

some have Transmembrane domains

35
Q

How many groups of Bcl-2 proteins are there?

A

3

Group 1

Group 2

Group 3 - contains BH3 only

(BH3 = dimerisation motif)

36
Q

Which are the anti-apoptotic proteins

A

Bcl-2, Bcl-xL (hooked on mitochondria)

37
Q

What are the pro-apoptotic proteins

A

Bid, Bad, Bax, Bak (move between cytosol and mitochondria)

Group 2 and 3

38
Q

Which 2 pathways does activation of the PI3 receptor (Growth factor receptor) cause

PI3 kinase stimulated by growth factors (e.g. EGF, insulin)

A
  1. ERK pathway (growth)

2. PI3 kinase pathway (survival, proliferation)

39
Q

What is PI3 kinase and what is it involved in

A

It is a lipid kinase (2 subunits - P110 and P85)

It is involved in growth control and cell survival

40
Q

Which anti-apoptotic protein kinase does PI3 kinase activate

A

PKB/Akt (via PIP3)

PI3 kinase converts PIP2 –> PIP3

41
Q

What is P13 kinase blocked by?

What effect does this have

A

Blocked by PTEN

Reduces cell survival

42
Q

4 ways in which PKB/Akt induces cell survival by blocking apoptosis

(intrinsic pathway)

A
  1. Phosphorylates and inactivates Bad
  2. Phosphorylates and inactivates caspase 9
  3. Inactivates FOXO Tfs (FOXOs promote expression of pro-apoptotic genes)
  4. Other, e.g. stimulates ribosome production and protein synthesis
43
Q

Explain how apoptosis is regulated by BH3 dimerisation

A
  1. Usually (GF present), Bad is inactive and phosphorylated in cytosol
  2. Bcl-xL/2 on mitochondria and form inactive dimers via BH3

GFs absent

  1. Bad dephosphorylated and released
  2. Displaces Bcl-2xL dimer
  3. Bax/Bak form a pore in the mitochondrial membrane, out of which cytochrome c leaks out
  4. Apoptosis triggered
44
Q

What is PTEN?

A

Lipid phosphatase

Means that we can alter lipid levels in the cell to control apoptosis/survival

45
Q

Which proteins can regulate extrinsic apoptosis

A

Inhibitor of Apoptosis Proteins (IAPs)

  • They bind to procaspases and prevent activation
  • bind to active caspases and inhibit their activity
46
Q

Name anti-apoptotic pathways for intrinsic pathway

A

Bcl-2, Bcl-xL

47
Q

Name anti-apoptotic pathways for the extrinsic pathway

A

FLIP, IAPS

48
Q

Name 2 therapeutic uses of apoptosis

A
  1. Kill harmful (oncogenic) cells - e.g. virally infected cells, cells w DNA damage
  2. Chemotherapeutic killing of tumour cells (e.g. dexamethasone stimulates DNA cleavage)

Year 2 Collin (114 decks)

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