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Cancer Y2 > Apoptosis > Flashcards

Apoptosis Flashcards

1
Q

5 reasons for apoptosis

A
  1. Harmful cells (e.g. cells with viral infection, DNA damage).
  2. Developmentally defective cells (e.g. B lymphocytes expressing antibodies against self-antigens).
  3. Excess/unnecessary cells (embryonic development: brain to eliminate excess neurons; liver regeneration; sculpting of digits and organs).
  4. Obsolete cells (e.g. mammary epithelium at the end of lactation).
  5. Exploitation - Chemotherapeutic killing of cells
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2
Q

Definition of necrosis

A

UNREGULATED CELL DEATH ASSOCIATED WITH TRAUMA, CELLULAR DISRUPTION AND AN INFLAMMATORY RESPONSE

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3
Q

Definition of apoptosis

A

REGULATED CELL DEATH; CONTROLLED DISASSEMBLY OF CELLULAR CONTENTS WITHOUT DISRUPTION; NO INFLAMMATORY RESPONSE

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4
Q

Execution of apoptosis: 9

A
  • Loss of microvilli and intercellular junctions
  • Cell shrinkage
  • Loss of plasma membrane asymmetry and the composition changes (phosphatidylserine lipid appears in outer leaflet)
  • Chromatin and nuclear condensation
  • Epithelium cannot afford a gap in their layer and so close around the cell that’s apoptosing (look at pic)
  • DNA fragmentation
  • Formation of membrane blebs
  • Fragmentation into membrane-enclosed apoptotic bodies
    PLASMA MEMBRANE REMAINS INTACT - NO INFLAMMATION
  • The apoptotic bodies are then phagocytosed by surrounding cells e.g. macrophages
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5
Q

What is APOPTOSIS-LIKE PCD

A

some, but not all, features of apoptosis e.g. Display of phagocytic recognition molecules before plasma membrane lysis

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6
Q

What is NECROSIS-LIKE PCD-

A

Variable features of apoptosis before cell lysis; ‘aborted apoptosis’

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7
Q

If you extract DNA from a cell and induce apoptosis, you will see X of the DNA

A

fragmentation

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8
Q

4 phases of apoptosis?

A
  1. Caspases
  2. Initiating the death programme:
     Death receptors (extrinsic)- external stimuli cause cell death
     Mitochondria (intrinsic)
  3. The Bcl-2 family (regulators of the whole cell death ting)
  4. Stopping the death programme
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9
Q

What are Caspases

A

‘Cysteine-dependent aspartate-directed proteases’

  • Executioners of apoptosis
  • Activated by proteolysis
  • Cascade of activation
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10
Q

Which/what are the initiator caspases

A
  • First ones to be triggered (e.g. caspase 2, 9, 10 and 8)
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11
Q

What special domain do caspase 2 and 9 contain

A

CARD - CAspase Recruitment Domain

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12
Q

What is the CAspase Recruitment Domain Card domain

A

this domain localises the caspase at particular sites within the cell and is homotypic

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13
Q

What special domain do caspase 8 and 10 contain

A

Death Effector Domain (DED)

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14
Q

What is the Death Effector Domain (DED)

A

this domain mediates homotypic binding protein-protein interactions

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15
Q

What are the effector caspases

A

Caspases 3, 6 and 7

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16
Q

What are the 2 types of caspase

A

Initiator (2, 9, 8, 10)

Effector (3, 6, 7)

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17
Q

What do effector caspases contain

A

p20 and p10

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18
Q

Where do you find the the Death Effector Domain (DED)

A

caspase 8 and 10

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19
Q

Where do you find the CAspase Recruitment Domain Card domain

A

caspase 2 and 9

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20
Q

What are caspases originally synthesised as

A

Procaspases (zymogens)

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21
Q

How many proteolytic cleavages liberate a caspase from a procaspase

A

2

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22
Q

What type of interactions do DED and CARD domains undergo

A

Homotypic

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23
Q

What do initiator caspases do

A

Initiate the caspase cascade and liberate effector caspase

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24
Q

What do effector caspases do (2)

A
  • They cleave and inactivate proteins or complexes (e.g. nuclear lamins leading to nuclear breakdown)
  • They also activate enzymes (including protein kinases, nucleases e.g. caspase activated DNase (CAD)) by direct cleavage, or cleavage of inhibitory molecules
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25
Q

2 mechanisms of caspase activation?

A

Receptor-mediated (extrinsic) pathways

Mitochondrial (intrinsic) pathway

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26
Q

What receptors activate caspases

A

Death receptors

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27
Q

Where do you find death receptors

A

Transmembrane with an intracellular cytoplasmic tail

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28
Q

What domain do you find on death receptor tails

A

Death domain

29
Q

What do death receptors do

A

Activate caspase

30
Q

When activated, what do death receptors attract

A

Adaptor proteins

31
Q

Example death receptors?

A

Fas, DR3,4,5,6 NGFR, TNFR1

32
Q

What adaptor proteins do death receptors recruit

A

FADD and FLIP

33
Q

What domains does FADD contain, what is it, what recruits it, and what does it do

A

FADD is an adaptor protein recruited by an activated death receptor
contain the DED domain and the Death Domain (DD)-> FAD activates the apoptotic pathway

34
Q

What domains does FLIP contain, what is it, what recruits it, and what does it do

A

FLIP is an adaptor protein recruited by an activated death receptor
proteins have 2 DED domains but have inhibitory activity

35
Q

Describe signalling through the Fas/Fas-ligand

A
  1. Receptor (Fas) trimerisation by ligand (Fas-L on lymphocyte)
  2. Recruitment of adapter protein (FADD) though its DD to the DD of Fas
  3. Recruitment and oligomerisation of procaspase 8 through its DED to the DED domain of FADD This is the DEATH INDUCING SIGNALLING COMPLEX (DISC)
36
Q

Describe activation of initiator procaspase 8

A
  1. Initiator procaspases bind, via their DED domains, to the DED domains of FADD which is bound via its DD domain to the DR
  2. This brings 3 initiator procaspase 8s into close contact, which allows cleavage
  3. This releases the active initiator caspase 8 tetramer
37
Q

Describe adaptor protein FLIPs actions (what does it compete with, what does it bind to)

A
  • FLIPs contain DED domains on their end terminals which can interact with DED domains on the FADD
  • FLIP has no proteolytic activity so it can compete with procaspase 8 to bind the DED domains on FADD

It can incorporate into receptor-procaspase complexes and interfere with cleavage to inhibit formation of caspase 8

38
Q

Describe mitochondrial regulation of apoptosis (intrinsic pathway)

A
  • Cellular stress causes loss of mitochondrial membrane potential
  • This causes release of cytochrome C and other factors as the mitochondria begin to die and their membrane breaks down
  • You get release of other apoptosis-inducing factors
  • An apoptosome complex is formed, which includes Apaf1 and caspase 9 -> This is the equivalent of DISC- it gathers proteins to cause degradation
39
Q

What does the apoptosome consist of

A

APAF-1 (apoptotic activating factor 1)
Cytochrome C
 ATP
 Procaspase 9

40
Q

Where is most of an apoptosomes constituents released from

A

Mitochondria

41
Q

Describe the structure of apoptosome (repeats, 2 domains)

A
  • At one end, APAF-1 contains a number of WD-40 repeats that are involved in protein-protein interactions and basically is a scaffolding protein that allows other molecules to bind to it
  • There is also an ATPase domain within APAF-1
  • At the other end of APAF-1 there is a caspase recruitment domain (CARD), which is also found on some initiator caspases (e.g. caspase 9)
42
Q

what does CytC bind to to form the apoptosome

A

WD40 repeats on APAF1

43
Q

What does APAF1 have on it

A

WD40 repeats

44
Q

How many CARD domains on an apoptosome

A

7

45
Q

What is the relationship between procaspase X, caspase X, and the apoptosome

A

X = 10

  • The CARD domains at the centre of the apoptosome can interact with the CARD domains on procaspase 9 (so seven procaspase 9s can bind to the apoptosome)
  • The close proximity of the procaspase 9s that bind to the CARD domains of the apoptosome means they can cross-cleave and activate eachother to produce caspase 9
46
Q

What is one of the major factors deciding whether a cell undergoes apoptosis or necrosis

A

ATP, apoptosis needs it

47
Q

What links the receptor-mediated and mitochondrial death pathways

A

Bid

- When one pathway is triggered, Bid can trigger the other pathway

48
Q

How does Bid trigger the intrinsic pathway

A

Bid promotes the release of cytochrome C from the mitochondrion, which triggers the mitochondrial death pathway

49
Q

How does Bid trigger the extrinsic pathway

A

Caspase 8 from the receptor-mediated pathway can cleave Bid, which enhances release of mitochondrial proteins, thus engaging the intrinsic pathway

50
Q

1 difference between the extrinsic and intrinsic pathway?

A

Intrinsic requires ATP for CytC to bind to WD40

51
Q

What family of proteins does Bid belong to

A

Bcl-2

52
Q

What characterises the Bcl-2 family

A

BH-3 homology domains

53
Q

What is special about group 3 Bcl-2 proteins

A

They only have BH3 domains and can dimerise

54
Q

Which Bcl-2 proteins are anti-apoptotic

A

Bcl-2

Bcl-XL

55
Q

Which Bcl-2 proteins are pro-apoptotic

A

Bid
Bax
Bad
Bak

56
Q

Describe inactivation of Bad

A
  • Phosphatidylinositol 3-kinase (PI3-K) is a lipid kinase involved in growth control and cell survival
  • It phosphorylates PIP2 to PIP3, which is then recognised by the adapter unit of PKB/Akt (protein kinase B)
  • PKB is then recruited to the cell membrane and it is activated It has anti-apoptotic effects
  • PKB phosphorylates and inactivates Bad (of the Bcl-2 family)
57
Q

Anti-apoptotic effect for PKB? (4)

A
  1. Phosphorylates and inactivates Bad
  2. Phosphorylates and inactivates caspase 9
  3. Inactivates FOXO transcription factors (FOXOs promote expression of apoptosis-promoting genes)
  4. Other, e.g. stimulates ribosome production and protein synthesis
58
Q

Describe activation of bad

A

GF absent -> PI3K pathway inactive -> PIP3 ungenerated -> PKB not recruited to membrane and activated -> Bad is dephosphorylated and released -> Bad goes to mitochondrial membrane and binds to anti-apoptotic Bcl-2 members which displaces pro-apoptotic Bcl-2 -> released pro-apoptotic Bcl-2 family members form a pore in mitochondrial membrane allowing CytC to escape and induce apoptosis

59
Q

What is PTEN and what does it do

A
  • PTEN is a lipid phosphatase that counteracts the production of PKB, therefore reducing the regulation of cell survival and promoting apoptosis
60
Q

What binds to procaspases and prevents their activation?

A

IAP Inhibitor of apoptosis proteins

61
Q

What binds to caspases and inhibits their action?

A

IAPs Inhibitor of apoptosis proteins

62
Q

IAPs Inhibitor of apoptosis proteins bind to and inhibit

A

Procaspases and caspases

63
Q

What counteracts the production of PKB

A

PTEN

64
Q

What mechanisms protect the intrinsic pathway

A
  • Bcl-2, Bcl-xL
65
Q

What mechanisms protect the extrinsic pathway

A
  • FLIP, IAPs
66
Q

What mechanisms protect the GF pathways

A

PI3’-K and PKB

67
Q

Example of proto-oncogene associated with apoptosis

A

Bcl-2 and PKB/Akt

68
Q

Example of TSG associated with apoptosis

A

PTEN - inactivation of this (which increases chance of apoptosis) leads to CANCER

Cancer Y2 (15 decks)

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