Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Canc > Cancer 10: apoptosis > Flashcards

Cancer 10: apoptosis Flashcards

1
Q

Why is programmed cell death (PCD) required

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.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How is apoptosis important in development of digits

A

Apoptosis is important in development, for example in the formation of the digits. The induction of apoptosis between digits allows the formation of hands and feet. If this process is dysfunctional, digits won’t separate.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Differentiate necrosis and apoptosis

A

Necrosis - unregulated cell death associated with trauma, cellular disruption and an inflammatory response

Apoptosis (programmed cell death) - regulated cell death; controlled disassembly of cellular contents without disruption; no inflammatory response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What occurs in necrosis

A

Plasma membrane becomes permeable

Cell swelling and rupture of cellular membranes

Release of proteases leading to autodigestion and dissolution of the cell

Localised inflammation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What happens to the chromatin and organelles duing necrosis

A

Cells and organelles swell. Chromatin condenses.

Membrane compromisd to fluid rushes in

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the two phases in apoptosis

A

Latent phase

Execution phase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What occurs in the latent phase of apopotiss

A

death pathways are activated, but cells

appear morphologically the same

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What happens during execution phase of apoptosis

A

Loss of microvilli and intercellular junctions

Cell shrinkage

Loss of plasma membrane asymmetry
(phosphatidylserine lipid appears in outer leaflet)

Chromatin and nuclear condensation

DNA fragmentation

Formation of membrane blebs

Fragmentation into membrane-enclosed apoptotic bodies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

T/F a common feature of apoptosis and necrosis is that the plasma membrane becomes permeable in both

A

F

Plasma membrane remains intact in apoptosis– no inflammation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

T/f chromatin condenses in both apoptosis and necrosis

A

T

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

State the sequence of apopotis

A

Microvilli contract/intercellular junctions break chromatin condenses

Cell shrinks- epithelium of neighbouring cells closes around it

Chromatin condeses around the nuclear periphery

Cell blebs violently…. chromatin condensation continues

Cell fragments into membrane-enclosed apoptotic bodies

Apoptotic bodies phagocytosed by neighburing cells and roving amcrophages

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How can the DNA modification in apoptosis be shown

A

DNA ladders on agarose gel…. due to fragmentation

TUNEL assay shows more flourescently-tagged bases due to more ‘ends’ due to the fragmentation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Differentiate necrosis and necrosis-like PCD

A

Unregulated cell death associated with cellular disruption and an inflammatory response

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Differentiate apoptosis and apoptosis-like PCD

A

Apoptosis (programmed cell death, PCD) - Regulated cell death; controlled disassembly of cellular contents; no inflammatory response

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

T/F there is clear distinction between apoptosis and necrosis of cells, no in between

A

F… there can be features of both

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the components of the mechanisms of apoptotic cell death

A
  1. Executioners (caspases)
  2. Initiating the death programme
    - Death recetpros
    - Mitochondria
  3. Bcl-2 family
  4. Stopping the death programme
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are caspases

A

Cysteine-dependent aspartate-directed proteases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What do caspases do, and how are they activated

A

Executioners of apoptosis

Activated by proteolysis

Cascade of activation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Categorise caspases

A

Initator caspases (2,9,10,8)

Effector caspases (3,6,7)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Outline the specific domains seen in caspases

A

CARD (caspase recruitment domain)… in caspase 2,9

DED (death effector domain) in caspace 10 and 8

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What do the specific domains within caspases bind

A

homotypic
protein-protein interactions
(cf. adaptors)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

T/F effector caspases also have specific domains

A

F

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Differentiate caspases to other cascade proteins

A

They are activated by cleavage, not phosphorylation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Where are the specific domains found within the initator caspases

A

On the N terminal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Outline protease maturation

A

Synthesised as pro-caspases (zymogens)

For INITIATOR caspases, the specific domain (DED/CARD) is cleaved. For the effecor casade, there is a smaller pro-domain which is cleaved

There is also then cleave at the sulphide double bond between the LS/SS regions

After the cleavage, you get folding of 2 large and 2 small chains to form an active L2S2 heterotetramer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Characterise caspace cascades

A

amplification
divergent responses
regulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is the function of initiator and effector caspases

A

Initiator caspases – trigger apoptosis by cleaving and activating..

Effector caspases – carry out the apoptotic programme

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What 2 tasks can effector caspases do

A

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

Activate enzymes
such as protein kinases or nucleases (e.g. Caspase-Activated DNase, CAD is a nuclease) by direct cleavage, or cleavage of inhibitory molecules

This can happen with monomers, or with multiprotein complexes (in the case of nuclear lamins break down)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

…..

A

…….

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

…….

A

…….

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Outline the mechanisms of caspase activation

A

Death by design – Receptor-mediated (extrinsic) pathways

Death by default – Mitochondrial (intrinsic) death pathway

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

T/F all cells contain death receptors

A

T

33
Q

Outline structure of the death receptors

A

Extracellular cysteine-rich domain

Single transcellular domain

Cytoplasmic tail (with a death domain)

34
Q

Where is the death domain found in the death receptor

A

In cytoplasmic tail

35
Q

Outline what follows the activation of death receptor

A

For example, FAS-Ligand might bind to FAS.

This then causes adaptor proteins to bind to the receptor

36
Q

What are the 2 types of adapter proteins associated with death receptors

A

FADD- ACTIVATE- contain DED and DD.

FLIP- INHIBITION. Contain DEATH EFFECTOR DOMAIN (DED and DED)

(remember that these specific domain regions are HOMOTYPIC)

37
Q

How does signalling occur through death receptors (e.g. Fas/Fas-liand)

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)
38
Q

What is oligomerisation

A

process that links monomeric compounds (e.g. amino acids, nucleotides or monosaccharides) to form dimers, trimers, tetramers, or longer chain molecules (oligomers)

39
Q

How is an initiator procaspase (e.g. initiator procaspase 8) activated

A

Procaspase 8 binds to the trimerised receptor tails/FADD adaptor protein (which is associated with the receptor tails by DD domains)

The inititiator procaspase which contains DED associates with the DED of the FADD. This forms DISC

The initiator procaspase is in close proximity to the other 2 initator procaspases (as one is assoaited with each receptor cytoplasmic tail), and TRANSCLEAVAGE occurs because of this

40
Q

Outline the two ways that the initator procaspase can be activated when they bind to the DED domain of the FADD adapter protein (which is linked to the death receptor)

A
  1. activated by conformational change on oligomerisation (I.e activated as its DED domain associates with the DED domain of the FADD adapter protein)
  2. Some initiator procaspases have intrinsic low catalytic activity – oligomerisation allows transcleavage

In transcleavage the initaitr procaspases can cleave each other too due to close proximity

41
Q

How many procaspases must be bound to the receptor to form an active tetramer

A

At least 2

42
Q

What is the structure of a procaspase

A

Prodomain + LS (long strand)+ SS (short strand)

Note the prodomains have specific domains in initiator caspases (CARD and DED), but this is not case for effector caspases

43
Q

What occurs following cleavage of the pro-caspase at the receptor

A

Active initiator caspase 8 tetramer released from receptor

44
Q

What inhibits activation of caspase 8 (the initiator caspase) at the death receptor

How

A

FLIP

FLIP contains 2 DED domains, so can bind to the FADD/receptor tails

Incorporates into receptor-procaspase complexes and interferes with transcleavage

45
Q

What is the effect of activated caspase 8

A

activates downstream effector caspases

46
Q

Outline how mitochonria regulate apoptosis

A

If loss of mitochondrial membrane potential (ΔΨ)

Cytochrome C is released

Other apoptosis inducing factors are released

The apoptosome complex is formed

47
Q

What can cause loss of mitochondrial membrane potential (ΔΨ)

A

Cellular stresses e.g. lack of or overstimulation by growth factors, DNA damage (p53), ROS

48
Q

What is the apoptosome composed of

A

Apaf1, caspase 9

49
Q

Outline the composition of the apoptosome (wheel of death)

A

7 X Apaf-1

apoptotic activating factor- 1

50
Q

What is the structure of the Apaf-1

A

There is a CARD domain (CAspase Recruitment Domain)

and many WD-40 repeats (protein protein-interactions)

51
Q

How is the apoptosome activated, and what is its effect

A

Cyt C (from mitochondrial damage) binds to WD40 domain USING ATP

This allows procaspase 9 to bind to the CARD domain

Oligomerisation brings multiple procaspase 9s close together, resulting in cleavage, activation and release as active caspase 9 tetramer, which initiates a caspase cascade leading to apoptosis

52
Q

T/f only certain Apaf-1 within the heptameric apoptosome can bind procaspase 9

A

F: each Apaf-1 in the heptameric apoptosome can potentially bind a procaspase 9

53
Q

How does the apoptosome/ wheel of death influence whether apoptosis or necrosis occurs

A

ATP!

The apoptosome requires ATP….

ENERGY LEVELS IN THE CELL DETERMINE WHETHER DEATH IS BY NECROSIS OR APOPTOSIS OR SOMETHING IN BETWEEN

54
Q

What is the relationship between the extrinsic and the intrnsic pathway of apoptosis

A

The death receptor binding etc. is all extrinsic

The mitochondrial damage/Cyt C binding to the apoptosome is the intrinsic pathway

Caspase 8 (activated by extrinsic pathway) cleaves Bid, which enhances release of the mitochondrial proteins, engaging the intrinsic pathway

55
Q

Which 2 factors can cause release of mitochondrial proteins to activate the apoptosome

A
  1. Mitochondrial damage

2. Caspase 8 activated through the extrinsic pathway via Bid

56
Q

Both the extrinsic and intrinsic pathway cause activation of which caspase

A

Caspase 3, which then leads to proteolysis and cell death

57
Q

Which family of proteins modulates apoptosis

A

Bcl-2 family proteins

58
Q

Classify Bcl-2 family proteins in terms of structure

A

Group 1-3

All contain dimerisation motif called BH3

Some contain other domains e.g. Transmembrane

Group 1: Bcl-2
Group 2: Bax
Group 3: Bid (activated by caspase 8 to cause mitochondrial damage), Bik and Bad these are BH3 only.

59
Q

t/f group 1, 2 and 3 all contain TM domain

A

Yes, group 1 and 2 do, but not necessarily all in group 3

60
Q

Give examples of antiapoptotic and pro-apoptotic proteins within the Bcl-2 apoptosis modulating family

A

Anti-apoptotic

   Bcl-2
   Bcl-xL

Pro-apoptotic

   Bid
   Bad
   Bax
   Bak
61
Q

Where are the anti-apoptotic and the pro-apoptocic Bcl-2 family proteins located in the cell

A

Anti apoptotic: MITOCHONDRIA

Pro apoptotic: move between Cytosol and Mitochondria, where they cause release of CyC/other apoptotic proteins(

62
Q

The PI3’-kinase signalling pathway is involved in what

A

Cell Cycle and Apoptosis Regulation

63
Q

T/f the PI3’-kinase signalling pathway occurs at the same receptor as the Ras/ERK pathway

A

T!

64
Q

Outline how the PI3’-kinase pathway is activated

A

Upon growth factor binding, PI3’K binds to p85 (an adapter protein bound to the receptor tyrosine kinase)

This then phsophorylates PIP2–>PIP3

This activates PDK1 then PKB/AKT.

AKT is anti-apoptotic

65
Q

What is PI3’K

A

Phosphatidylinositol 3’-kinase (PI3’-K) – a lipid kinase (not a protein kinase) involved in growth control and cell survival

PIP3 has phopshorylation on the 3, 4 and 5 position. Whereas PIP2 only has phosphorylation on the 4 and 5 position

It is essentially part of the plasma membrane

66
Q

How is PI3-k different to other kinases

A

It phosphorylates a phospholipid not a protein

67
Q

What does PKB/Akt bind to

A

The PH domain of these proteins bind to the PIP3

68
Q

What is the effect of PKB/Akt

A

Phosphorylates and inactivates Bad

Phosphorylates and inactivates caspase 9

Inactivates FOXO transcription factors (FOXOs promote expression of apoptosis-promoting genes) such as p27Kip and apoptotic protein Fas
ligand

Other, e.g. stimulates ribosome production and protein synthesis

69
Q

Which transcription factos promote transcription of pro-apoptotic genes

A

FOXOs

70
Q

How does the PKB/Akt proteins, from the GF pathways, interact with apoptosis regulation by mitocondria

A

Normally Bad is is phosphorylated and inactivated by PKB/Akt.

This allows Bax or Bak to be bound to Bcl2, and bcl2-xL (group 1 of the bcl2 family)

However, when GF is absent, Bad will displace Bax and Bak, and Bad will bind to Bcl2 or Bcl-xL instead.

This then releases the Bax or Bak, such that they combine to form a pore, out of which mitochondrial contents (like Cyt C) can flow, and activate apoptosis

71
Q

How are Bcl2 and Bax linked

A

Via BH3 domains (common to all Bcl2 proteins)

72
Q

What type of molecule is PTEN

A

(Llipid phosphatase)

73
Q

How does PTEN work to inhibit PI3’-K pathway

A

It removes the phosphate from PIP3, forming PIP2, which cannot activate the PKB/Akt proteins which induce cell survival and protein syntehsis

74
Q

Compare PTEN and PI3’-K

A

PTEN is a lipid phosphatase and PI3’-K is a lipid kinase….

allows for control of cell survival easily

75
Q

What are the anti-apoptotic pathways for the intrinsic and extrinsic pathway

What other antiapoptotic pathway is there

A

INTRINSIC: Bcl-2, Bcl-xL (which prevent BAX and Bak from heterodimertising to form the pore allowing escape of Cyt C, inducing the apoptosome, and eventually activation of caspase 9

EXTRINSIC: FLIP and IAPs (inhibitor of Apoptosis Proteins)

Growth factor pathways via PI3’-K and PKB/Akt

76
Q

What are inhibitors of apoptosis proteins

A

regulate Programed Cell Death via Extrinsic pathway

Bind to procaspases and prevent activation

Bind to active caspases and inhibit their activity

77
Q

How can cancer cells avoid apoptosis

A

Apoptosis regulators as

oncogenes or tumour suppressors?

78
Q

How can programmed cell death be used therapeutically

A

Harmful (oncogenic) cells can be virally infected to cause DNA damage

Chemotherapeutic killing of tumour cells, e.g. Dexamethasone stimulates DNA cleavage, which damages DNA and sends these cells down the apoptotic pathway

Canc (16 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions