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Y2 MCD - Cancer - Laz > Apoptosis > Flashcards

Apoptosis Flashcards

1
Q

Define Necrosis.

A

Unregulated cell death associated with trauma, cellular disruption and an inflammatory response

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2
Q

Define Apoptosis.

A

Regulated cell death; controlled disassembly of cellular contents without disruption – no inflammatory response

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3
Q

Describe the process of necrosis.

A

The plasma membrane becomes more permeable – the cell swells and the membrane ruptures
Proteases are released leading to dissolution and autodigestion of thecell
There is localised inflammation

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4
Q

What are the two phases of apoptosis? Describe them.

A

Latent phase
 Death pathways are activated, but cells appear morphologically the same
Execution phase:
 Loss of microvilli and intercellular junctions
 Cell shrinkage
 Loss of plasma membrane asymmetry
 Chromatin and nuclear condensation
 DNA fragmentation
 Formation of membrane blebs
 Fragmentation into membrane enclose apoptotic bodies (these are then taken up by macrophages)

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5
Q

What is an important feature of apoptosis that distinguishes itfrom necrosis?

A

Plasma membrane remains intact – no inflammation

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6
Q

What DNA modification is seen during apoptosis?

A

Fragmentation of DNA ladders (seen in agarose gel)

Formation of more ends, which are labelled by adding an extra fluorescently-labelled tag in a TUNEL assay

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7
Q

What other types of cell death are there other than necrosis and apoptosis?

A

Apoptosis-like cell death
Necrosis-like cell death (sort of like an aborted apoptosis that ends up being necrosis)
NOTE: cell death is GRADED

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8
Q

What are caspases?

A

Cysteine-dependent aspartate-directed proteases
They are the executioners of apoptosis
They are activated by cleavage

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9
Q

Which caspases are effector caspases?

A

3, 6 and 7

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10
Q

Which caspases are initiator caspases?

A

2, 8, 9 and 10

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11
Q

Describe the structure of effector caspases.

A

They are single chain polypeptides consisting of a small and large subunit
The subunits are released by proteolytic cleavage

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12
Q

Describe the structure of initiator caspases.

A

They have the same two subunits found in effector caspases but they also have a targeting subunit (protein-protein interacting domain)

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13
Q

What are the two types of targeting subunit that initiator caspases can have?

A

CARD – caspase recruitment domain

DED – death effector domain

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14
Q

How are active caspases formed?

A

Cleavage of inactive procaspases is followed by the folding of 2 largeand 2 small chains to form an active L2S2 heterotetramer

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15
Q

What are the two mechanisms of apoptosis

A

Death by design (receptor-mediated)

Death by default (mitochondrial (intrinsic) death pathway)

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16
Q

Describe the structure of death receptors.

A

Cysteine-rich extracellular domain
Transmembrane domain
Intracellular tail with a death domain (DD)

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17
Q

What are the two important adaptor proteins in the death by design pathway and how are they different?

A

FADD – positive regulator that promotes cell death – DED + DD
FLIP – negative regulator – DED + DED

18
Q

Describe signalling of apoptosis through Fas.

A

 Fas ligand binds to Fas receptor (on CTLs) and the Fas receptors undergo trimerisation, which brings the three DDs together
 The trimerised DDs recruit FADD, which binds via its own DD
 FADD then recruits and oligomerises procaspase 8 through the DED of procaspase 8
 Binding of procaspase 8 to FADD forms DISC (death-induced signalling complex)
 DISC formation results in cross-activation of procaspase 8
 Active caspase 8 is released, which then activates effector caspases

19
Q

Describe the important of oligomerisation in this pathway.

A

Some initiator caspases have intrinsic low catalytic activity
Oligomerisation brings them close enough together to allow transcleavage
Also, at least 2 procaspases are required to form an active caspase

20
Q

Describe how FLIP acts as an inhibitor of apoptosis

A

FLIP is evolutionarily related to caspases but has lost its catalytic activity
It has two DED domains and can compete with procaspase 8 to bind to the DED domains of FADD
It can incorporate into receptor-procaspase complexes and interfere with transcleavage

21
Q

As an overview, describe death by default.

A

Cellular stress causes a change in mitochondrial membrane potential
This leads to release of cytochrome C from the mitochondrion
This stimulates formation of the apoptosome complex

22
Q

What does the apoptosome consist of?

A

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

23
Q

Describe the domains found within APAF-1.

A

CARD domain
ATPase domain
WD-40 repeats (protein-protein interactions)

24
Q

Explain fully, how death by default leads to caspase activation.

A

The cytochrome C released from the mitochondria bind to the WD-40 repeats of APAF-1 and make it form a heptamer structure (apoptosome)
This requires ATP
It has 7 CARD domains in the middle, which can interact with CARD domains of procaspase 9
Seven procaspase 9 bind via their CARD domains to the apoptosome and their close contact allows them to cross-cleave each other to generate activate caspase 9

25
Q

What pro-apoptotic protein links the death by default and death by design pathways? Explain how it works.

A 
Bid  
Caspase 8 (generated by the death by design pathway) cleaves Bid, which travels to the mitochondrion and promotes the release of cytochrome C – thus triggering the mitochondrial death pathway
26
Q

How can energy levels of a cell show whether a cell is going through apoptosis or necrosis?

A

Apoptosis requires energy whereas necrosis does not

27
Q

What is an important family of proteins that act as intrinsicmodulators of apoptosis?

A

Bcl-2 family

28
Q

There are three main groups of Bcl-2 proteins. What is common toall three groups?

A

BH3 domain – this is a dimerisation motif, which allows members of the family to form dimers with each other

29
Q

What are the anti-apoptotic Bcl-2 proteins and where are they found?

A

Bcl-2
Bcl-xL
They are found localised on the mitochondrial membrane

30
Q

What are the pro-apoptotic Bcl-2 proteins and where are they found?

A 
Bid 
Bad 
Bax 
Bak 
These are found in the cytoplasm and in the mitochondrial membrane
31
Q

Other than Ras signalling, what other pathway does growth factor binding to growth factor receptors activate?

A

PI3-kinase

32
Q

What type of molecule is PI3-K?

A

Lipid kinase

33
Q

What are the main subunits of PI3-K?

A

Adaptor subunit
Targeting subunit
Catalytic subunit

34
Q

What is the main action of PI3-K?

A

PI3-K converts PIP2 to PIP3

35
Q

What effect does this action have that leads to inhibition of apoptosis?

A

PIP3 is recognised by the adaptor subunit of Protein Kinase B (PKB/Akt)
This allows PKB to move to the cell membrane where it becomes activated
PKB phosphorylates and inactivates Bad

36
Q

Describe the arrangement of the anti-apoptotic and pro-apoptotic proteins when growth factor signalling and the PI3-K pathway is active.

A

This means PI3-K can produce PIP3 – so PKB/Akt is activated meaning that Bad is phosphorylated and inactivated
Bad is held in an inactive heterodimer with 14-3-3
On the mitochondrial membrane, Bak and Bax are held in inactive heterodimers with Bcl-2 and Bcl-xL

37
Q

Describe how loss of growth factor signalling can lead to apoptosis.

A

This means loss of activation of the PI3K pathway so less PIP3 produced so less activation of PKB/Akt
Bad gets dephosphorylated and dissociated from its inactive heterodimer
Bad then moves to the mitochondrial membrane and binds to the anti-apoptotic proteins (Bcl-2 and Bcl-xL) via its BH3 domain
This displaces Bax and Bak from their inactive heterodimers
So Bax and Bak then form a pore in the mitochondrial membrane allowing the release of cytochrome C from the mitochondrion – this leads to apoptosis

38
Q

Summarise the effects of PKB/Akt in promoting cell survival.

A

Phosphorylates and inactivated Bad
Phosphorylates and inactivates caspase 9
Inactivates FOXO transcription factors (FOXOs promote the expression of apoptosis-promoting genes)

39
Q

Name two extrinsic regulators of apoptosis and describe their actions.

A

PTEN
 Lipid phosphatase
 Counteracts the activation of PKB
 Reduces cell survival and promotes apoptosis
IAPs (Inhibitor of Apoptosis proteins)
 Binds to procaspases and prevents their activation
 Can bind to activate caspases and inhibit their activity

40
Q

Are the following tumour suppressor genes or oncogenes?

a. Bcl-2
b. PTEN
c. PKB/Akt

A

a. Bcl-2
Oncogene – increased activation would mean reduced likelihood of apoptosis (cancers are anti-apoptotic)
b. PTEN
Tumour suppressor gene –inactivation will mean reduced likelihood of apoptosis
c. PKB/Akt
Oncogene

Y2 MCD - Cancer - Laz (15 decks)

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