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Y2 Cancer > Apoptosis > Flashcards

Apoptosis Flashcards

1
Q

What may cause programmed cell death

A 
Harmful cells
Developmentally defective cells
Excess/unnecessary cells
Obsolete cells
Exploitation
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2
Q

Define necrosis

A

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

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3
Q

Define Apoptosis

A

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

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4
Q

Describe the process of necrosis

A
  1. Plasma membrane becomes 2. permeable
    Cell swelling and rupture of cellular membranes
  2. Release of proteases leading to autodigestion and dissolution of the cell
  3. Localised inflammation
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5
Q

What occurs in the latent phase of apoptosis

A

Death pathways are activated, but cells appear morphologically the same

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6
Q

What occurs in the execution phase of apoptosis

A

Loss of microvilli, intercellular junctions and plasma membrane asymmetry (phosphatidylserine lipid appears in outer leaflet)
Cell shrinkage
Chromatin and nuclear condensation
DNA fragmentation
Formation of membrane blebs
Fragmentation into membrane-enclosed apoptotic bodies

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7
Q

How is the apoptotic body removed

A

Phagocytosis by surrounding cells e.g. macrophages

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8
Q

Describe DNA modification in apoptosis can be viewed

A

DNA ladders - fragmentation

TUNEL - DNA fragmentation leads to more ‘ends’, labelled by adding a fluorescently tagged base

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9
Q

Define apoptosis-like PCD

A

Some, but not all, features of apoptosis.

Display of phagocytic recognition molecules before plasma membrane lysis

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10
Q

Define Necrosis-like PCD

A

Variable features of apoptosis before cell lysis; “Aborted apoptosis”

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11
Q

What are the 4 steps of the apoptotic cell death mechanism

A
  1. Caspases (executioners)
  2. Death receptors and mitochondria
  3. Bcl-2 family
  4. Stopping the death programme
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12
Q

What is the full name of caspases

A

Cysteine-dependent aspartate-directed proteases

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13
Q

What is the role of caspases in apoptosis

A

Executioners of apoptosis
Activated by proteolysis
Cascade of activation

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14
Q

What is the CARD and DED

A

Targeting subunits found on imitator caspases
CARD - Caspase Recruitment Domain
DED - Death Effector Domain

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15
Q

What are the initiator caspases and describe their structure

A

Caspase 2, 8, 9 and 10
Have that same pair of subunits, but in addition have an extra TARGETING subunit (protein-protein interacting domain) which directs them to a particular location
DED found on caspase 8 and 10

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16
Q

What are the effector caspases and describe their structure formation

A

Caspase 3, 6, and 7
Similar molecular organization
Starts off as a single chain polypeptide with two subunits (large + small) that are released by proteolytic cleavage during maturation

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17
Q

Explain the process of caspase maturation

A

Cleavage of the inactive procaspase precursor is followed by folding of 2 large and 2 small chains to form an active L2S2 heterotetramer

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18
Q

What are the roles of imitator and effector caspases in the caspase cascade

A

Initiator - trigger apoptosis by cleaving and activating effector caspases

Effector - carry out the apoptotic programme

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19
Q

How do effector caspases execute the apoptotic programme

A

Cleave and inactivate proteins or complexes (e.g. nuclear lamins leading to nuclear breakdown)

Activate enzymes by direct cleavage, or cleavage of inhibitory molecules
(incl. protein kinases; nucleases, e.g. Caspase-Activated DNase, CAD)

20
Q

What are the mechanisms of caspase action

A

Death by design – Receptor-mediated (extrinsic) pathways

Death by default – Mitochondrial (intrinsic) death pathway

21
Q

Describe the structure of death receptors

A 
Found on all cells
Consists of: 
Extracellular cysteine- rich domain
Single transcellular domain 
Cytoplasmic tail with a “death domain”
22
Q

When are death receptors activated

A

when they encounter secreted or transmembrane trimeric ligands (eg TNF or Fas) called “DEATH LIGANDS”

23
Q

Which are the two adaptor proteins involved in receptor-mediated apoptosis

A

Activation - FADD

Inhibition - FLIP (allows regulation)

24
Q

Which domains are contained in FADD and FLIP

A

FADD - DED and DD
FLIP - DED x 2
(DED = death effector domain)
(DD= death domain)

25
Describe the process of signalling through death receptors using Fas receptor as an example
1. Receptor (Fas) trimerisation by ligand (Fas-L on lymphocyte) 2. Recruitment of adapter protein (FADD) through DD 3. Recruitment and oligomerisation of procaspase 8 through its DED to FADD DED 4. Formation of the Death-Inducing-Signalling Complex (DISC) 5. Cross-activation of procaspase8, whereby they cleave each other within the complex (due to close proximity). The active caspase 8 is then released, and it cleaves effector caspases to execute the death programme
26
What is the role of FLIP in death receptor activation of caspase 8
Inhibits death receptor activation of caspase 8 No proteolytic activity Competes with procaspase via DED for binding to receptor tails
27
Describe the mitochondrial regulation of apoptosis
1. Cellular stresses cause loss of mitochondrial membrane potential (ΔΨ) 2. Release of cytochrome c and other apoptosis- inducing factors 3. Formation of the apoptosome complex
28
What does the apoptosome contain
APAF-1 (apoptotic activating factor 1) cytochrome C ATP procaspase 9
29
Describe the structure of the Apaf-1LC
At one end, Apaf1 contains a number of repeats that are involved in protein-protein interactions (WD-40) At the other end there is an ATPase domain. At the front there is a caspase recruitment domain (CARD), which is also found in some initiator caspases (e.g. caspase 9)
30
Describe the process of death by default
1. Cytochrome C binds to the WD-40 repeats on Apaf-1 2. Heptamer (apoptosome) formation, requires ATP 3. The CARD domains at the centre of the heptamer are capable of interacting with CARD domains on procaspase-9 (7 bind in total) 4. The close proximity of the procaspase 9s mean they can cross- cleave and activate each other to produce caspase 9. 5. This is released and is able to trigger the caspase cascade > apoptosis
31
How does energy levels in the cell affect the method of cell death
ATP - apoptosis | No ATP - necrosis
32
How is the receptor-mediated pathways distinguished from the mitochondria-mediated when one imitates the other
Mitochondria-mediated pathway requires ATP
33
What is Bid and what does it do
Protein which links receptor-mediated and mitochondria-mediated pathways together
34
How doe Bid carry out its function
Bid is cleaved by caspase Once it is cleaved, it can go to the mitochondria and promote the release of cytochrome C, therefore recruiting the mitochondria-mediated pathway
35
Which molecules are involved in modulation/regulation of apoptosis
The Bcl-2 Family Growth Factors Phosphatidylinositol 3-kinase (PI3-K) Extrinsic regulators
36
Which domain do all 3 groups of Bcl-2 family proteins contain and what is it function
BH3 domain BH3 is a protein-protein interaction (dimerization) motif that allows proteins of this family to associate and dimerise with each other
37
What are the two categories of Bcl-2 family proteins and where are they found + give examples
Anti-apoptotic - localised to the mitochondrial membrane (eg Bcl-2 and Bcl-xL) Pro-apoptotic - move between the cytosol and the mitochondrial membrane (eg Bid, Bad and Bax)
38
What is Phosphatidylinositol 3-kinase and what is it structure
PI3-K is a lipid kinase involved in growth control and cell survival Has a targeting subunit, and adaptor subunit and a catalytic subunit
39
What is the role of PI3-K
Phosphorylates PIP2 to PIP3, which is recognized by the adapter subunit of PKB (protein kinase B) [also known as Akt]
40
Explain how PKB/Akt induces cell survival by blocking apoptosis
1. PKB is recruited to the cell membrane and is activated, with anti-apoptotic effects 2. PKB phosphorylates the Bad, and causes it to be help in an inactive heterodimer in the cytoplasm 3. Other pro-apoptotic proteins (including Bid + Bax) are held in their inactive heterodimers by the BH3 domains of the anti-apoptotic Bcl-2/xL proteins 4. With the pro-apoptotic proteins held in inactive heterodimers, cell survival and proliferation are promoted
41
What are the other roles of protein kinase B
Phosphorylates and inactivates caspase 9 Inactivates FOXO transcription factors (FOXOs promote expression of apoptosis-promoting genes) Other, e.g. stimulates ribosome production and protein synthesis
42
What is PTEN and what does it do
PTEN is a lipid phosphatase that counteracts the production of PKB therefore reducing the regulation of cell survival and promoting apoptosis
43
What are IAPs and what do they do
IAPs (inhibitors of apoptosis proteins) regulate programmed cell death by binding to procaspases and preventing their activation, and binding to active caspases and inhibiting their activity.
44
How can cancer cells avoid apoptosis
Tumour suppressors (PTEN) are often deleted/inactivated in many cancers Proto-oncogenes will promote apoptosis Oncogenes (mutated from proto-oncogenes) are often overexpressed in cancers, eg Bcl-2 and PKB
45
What are the therapeutic uses of apoptosis in cancer
Harmful (oncogenic) cells (e.g. cells with viral infection, DNA damage) Chemotherapeutic killing of tumour cells, e.g. Dexamethasone stimulates DNA cleavage

Y2 Cancer (16 decks)

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