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Y2 MCD Cancer > cell cycle > Flashcards

cell cycle Flashcards

apoptosis: explain the difference between necrosis and apoptosis, recall cellular mechanisms which execute the apoptotic response, and recall how the Bcl-2 family proteins can modulate apoptosis (79 cards)

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1
Q

5 reasons for apoptosis (programmed cell death)

A

harmful cells, developmentally defective cells, excess/unnecessary cells, obsolete cells, exploitation

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2
Q

technique for labelling apoptotic cells, and how does it work

A

tunel technique, as it labels fragments of DNA (nucleus in yellow)

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3
Q

define necrosis

A

unregulated cell death association with trauma, cellular disruption and an inflammatory response

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4
Q

define apoptosis

A

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

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5
Q

stages of necrosis

A

plasma mebrane becomes permeable -> cell swelling and rupture of cellular membranes -> release of proteases leading to autodigestion and dissolution of cell -> localised inflammation as phagocytic cells clear up debris (healthy cells either side divide to fill gap)

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6
Q

2 phases of apoptosis

A

latent and execution

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7
Q

what happens in latent apoptosis

A

death pathways activated, but cells appear morphologically the same

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8
Q

7 stages of execution phase

A

loss of microvilli and intercellular junctions -> cell shrinkage -> loss of plasma membrane asymmetry (phosphatidylserine lipid appears in outer leaflet, as imbalance in lipid composition) -> chromatin and nuclear condensation -> DNA fragmentation -> formation of membrane blebs -> fragmentation into membrane-enclosed apoptotic bodies -> apoptotic bodies phagocytosed by neighbouring cells and macrophages

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9
Q

what happens during apoptosis to ensure no inflammation

A

plasma membrane remains intact

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10
Q

DNA modification in apoptosis

A

DNA fragments, leading to more “ends” which are labelled by adding an extra fluorescently-tagged base

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11
Q

4 types of cell death (graded response)

A

necrosis, apoptosis, apoptosis-like PCD, necrosis-like PCD

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12
Q

what is apoptosis-like programmed cell death

A

some (but not all) features of apoptosis, with a display of phagocytic recognition molecules before plasma membrane lysis

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13
Q

what is necrosis-like programmed cell death

A

variable features of apoptosis before cell lysis (aborted apoptosis)

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14
Q

4 mechanisms of apoptotic cell death

A

executioners -> initiating death programme -> Bcl-2 family -> stopping death programme

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15
Q

what executes apoptotic cell death

A

caspases

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16
Q

what 2 things initiate death programme

A

death receptors, mitochondria

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17
Q

what are caspases (full name)

A

cysteine-dependent aspartate-directed proteases

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18
Q

what are caspases activated by

A

proteolysis (synthesised in cell as zymogens, but activated by cleavage)

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19
Q

2 types of caspases

A

initiator (8, 9), effector (3, 7, 6, 2, 1)

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20
Q

what prodomains are present in caspases 2 and 9

A

CARD (caspase recruitment domain); also p20, p10

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21
Q

what prodomains are present in caspases 10 and 8

A

DED (death effector domain); also p20, p10

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22
Q

how do caspases dimerise

A

homotypic protein-protein interactions (dimerise with same caspase), ensuring localisation

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23
Q

effector caspases

A

3, 6, 7 (just p20, p10)

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24
Q

caspase maturation pathway

A

procaspases (zymogens) -(proteolytic cleavage, releasing inactive prodomains)-> active enzyme

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25
in the caspase maturation pathway, what is cleavage of inactive procaspase precursor followed by
folding of 2 large and 2 small chains to form an active L2S2 heterotetramer
26
3 functions of caspase cascades
amplification, divergent responses, regulation
27
function of initiator caspases (8, 9)
trigger apoptosis by cleaving and activating
28
function of effector caspases (3, 7, 6, 2, 1)
carry out apoptotic programme
29
function of caspase 10
regulator
30
2 things effector caspases do to execute apoptotic programme
cleave and inactivate proteins or complexes (e.g. nuclear laminins to cause nuclear breakdown), or activate enzymes
31
example of enzyme activated by effector caspases
protein kinases and nucleases, such as caspase activated DNase (CAD)
32
2 ways effector caspases activate enzymes
direct cleavage, cleavage of inhibitory molecules
33
2 mechanisms of caspase activation
death by design (receptor-mediated extrinsic pathways), death by default (mitochondrial intrinsic death pathway)
34
death by design (receptor-mediated extrinsic pathways): death receptor stage
secreted or transmembrane ligands (trimeric) bind to EC cysteine rich domains (all have IC death domain - DD)
35
death by design (receptor-mediated extrinsic pathways): ligands in apoptosis vs normal
trimeric in apoptosis, dimeric when normal
36
death by design (receptor-mediated extrinsic pathways): adapter proteins activation and inhibition
activation FADD consists of DED (death effector domain) and DD (death domain); inhibition FLIP consists of 2x DED domains
37
death by design (receptor-mediated extrinsic pathways): what do DD and DED domains bind to
similar domains on other proteins
38
death by design (receptor-mediated extrinsic pathways): signalling through death receptors e.g. Fas/Fas-ligand
receptor (Fas) trimerisation by death ligand (Fas-L on lymphocyte) -> IC recruitment of adapter protein (FADD) through its DD to DD of Fas -> recruitment and oligomerisation of procaspase 8 through DED to FADD DED -> formation of death-inducing signalling complex (DISC)
39
death by design (receptor-mediated extrinsic pathways): where is Fas upregulated
on infected cells
40
death by design (receptor-mediated extrinsic pathways): what does initiator procaspase 8 oligomerisation result in
cleavage and activation (initiator procaspase 8 and trimerised receptor tails/FADD) -> active initiator caspase 8 tetramer released from receptor
41
death by design (receptor-mediated extrinsic pathways): 2 types of initiator procaspases catalytic activity
some have intrinsic low catalytic activity (oligomerisation allows transcleavage), others activated by conformational change on oligomerisation
42
death by design (receptor-mediated extrinsic pathways): how many procaspases are required to form active tetramer
at least 2 (one must cleave the other)
43
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-
44
death by design (receptor-mediated extrinsic pathways): what is death receptor activation of caspase 8 (initiator caspase) inhibited by
FLIP (2x DED domains), with long form containing p20 and p10, but short form not having these
45
death by design (receptor-mediated extrinsic pathways): how do FLIP inhibit death receptor activation of procaspase 8
no proteolytic activity so competes with procaspase 8 for binding to receptor tails/FADD via DED domains, so incorporates into receptor-procaspase complexes and interferes with transcleavage
46
death by design (receptor-mediated extrinsic pathways): what does caspase 8 (initiator caspase) activate
downstream effector caspases
47
death by default (mitochondrial intrinsic death pathway): 4 stages
loss of mitochondrial membrane potential (ΔΨ) -> release of cytochrome c -> release of other apoptosis-inducing factors -> formation of apoptosome complex
48
death by default (mitochondrial intrinsic death pathway): what causes a loss of mitochondrial membrane potential, causing release of cytochrome c
cellular stresses e.g. lack of/overstimulation by growth factors, DNA damage (p53), ROS
49
what does the apoptosome (wheel of death) contain
apaf-1 (apoptotic activating factor-1; contains CARD, ATPase and WD-40 repeats)), cytochrome c, ATP, procaspase 9
50
how many molecules form apoptosome
7
51
what domain is at centre of apoptosome
CARD (caspase recruitment domain)
52
what domain is at edge of apoptosome
WD-40 repeats (protein-protein interactions)
53
what does cytochrome c bind to
WD40 repeats
54
what can each apaf-1 in heptameric apoptosome potentially bind to
procaspase 9 via CARD domain of apaf-1
55
what does oligomerisation bring together, and what does this result in
oligomerisation brings multiple procaspase 9s close together, resulting in cleavage, activation and release as active caspase 9 tetramer
56
what does active caspase 9 tetramer initiate
caspase cascade leading to apoptosis
57
what does the apoptosome require, and consequently what determines whether cell death is by necrosis or apoptosis
ATP, so if present cell undergoes apoptosis, but if not cell undergoes necrosis
58
what are the principal mechanisms of apoptosis
bid links receptor and mitochondrial death pathways
59
principal mechanisms of apoptosis: what does caspase 8 cleave, and what does this enhance (both pathways activated)
cleaves Bid which enhances release of mitochondrial proteins, engaging intrinsic pathway (shared effector programmes, with caspase 8 enhancing mitochondrial intrinsic cell death)
60
what are the modulators of apoptosis
Bcl-2 family proteins
61
domains of Bcl-2
BH4, BH3, BH1, BH2, transmembrane (attached to mitochondrial membrane)
62
2 anti-apoptotic Bcl-2 family proteins
Bcl-2, Bcl-xL
63
location of anti-apoptotic Bcl-2 family proteins
mitochondria
64
4 pro-apoptotic Bcl-2 family proteins
Bid, Bad, Bax, Bak
65
location of pro-apoptotic Bcl-2 family proteins
move between cytosol and mitochondria
66
how is growth factor receptor used by PI3'-kinase used for growth
growth factor -> binds to growth factor receptor -> Ras -> ERK -> growth
67
PI3'-kinase signalling pathway in cell cycle and apoptosis regulation to ensure survival and proliferation
growth factor -> binds to growth factor receptor -> PI3'-K -> PDK-1 -> PKB/Akt -> survival and proliferation
68
PI3'-kinase signalling pathway in cell cycle and apoptosis regulation: what is PI3'-K and what does it do to ensure cell survival
lipid kinase involved in growth control and cell survival by activating (phosphorylating) protein kinase PKB/Akt (from PIP2 to PIP3 on membrane), which is anti-apoptotic
69
2 sections of PI3'-kinase
p85 (adapter) and p110 (kinase)
70
how does PKB/Akt block apoptosis (4 things)
phosphorylates and inactivates Bad and caspase 9, inactivates FOXO transcription factors (promote expression of apoptosis-promoting genes), other e.g. stimulates ribosome production and protein synthesis
71
regulation of apoptosis by Bcl-2 family proteins via BH3 heterodimerisation: cell survival
growth factor present causes PKB/Akt production -> in mitochondrial matrix, heterodimers Bcl-2 and Bax inactive by BH3-BH3 domains, and phospho-Bad inactive in cytosol
72
regulation of apoptosis by Bcl-2 family proteins via BH3 heterodimerisation: apoptosis
growth factor absent -> in mitochondrial matrix, Bad dephosphorylated and released -> displaces Bcl-2/-xL from Bak -> Bax/Bak pore in mitochondria -> release of cytochrome C
73
what counteracts PI3'-K signalling
PTEN (lipid phosphatase)
74
what does PTEN do to counteract PI3'-K signalling
reverses PI3'-K catalysed reaction, so dephosphorylates and prevents anti-apoptosis
75
what regulates apoptosis extrinsic pathway
inhibitor of apoptosis proteins (IAPs)
76
2 ways inhibitor of apoptosis proteins (IAPs) regulate apoptosis extrinsic pathway
bind to procaspases and prevent activation, bind to active caspases and inhibit their activity
77
3 cytoprotective/anti-apoptotic pathways
intrinsic pathway (Bcl-2/-xL), extrinsic pathway (FLIP, IAPs), growth factor pathways via PI3'-K and PKB/Akt
78
how do cancer cells avoid apoptosis
apoptosis regulators as oncogenes or tumour suppressors
79
2 therapeutic uses of apoptosis
harmful (oncogenic) cells (viral infection/DNA damage), chemotherapeutic killing of tumour cells e.g. dexamethasone stimulates DNA cleavage

Y2 MCD Cancer (20 decks)

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