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Cancer Cell and Molecular Biology > apoptosis > Flashcards

apoptosis Flashcards

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1
Q

what are the morphological features of apoptosis?

A
  • cell shrinkage
  • plasma membrane blebbing
  • chromatin condensation
  • shrinking of nucleus
  • chromatin degradation
  • loss of mitochondrial membrane potential
  • cell breaks into apoptotic bodies
  • translocation of phosphatidylserine to outer lipid bilayer
  • secretion of pro-inflammatory cytokines
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2
Q

how is phosphatidylserine involved in apoptosis?

A

after translocation to the outer lipid bilayer, it binds to receptors on phagocytic cells like macrophages and dendritic cells that engulf the cell fragments

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3
Q

which protein kinase mediates membrane blebbing?

A

ROCK-I

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4
Q

what is the activation of ROCK1 dependent on?

A

1- binding to a small GTP binding protein (Rho)

2- binding to arachidonic acid

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5
Q

what is the role of caspase 3 in activation of ROCK1?

A

cleaves ROCK1 so it is no longer dependent on GTP-Rho or arachidonic acid - becomes cons. active

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6
Q

outline the extrinsic pathway

A

death ligand binds death receptor, recruiting adaptor proteins and cleavage of initiator caspase, which activates executioner caspase

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7
Q

outline the intrinsic pathway

A

DNA damage/stress leads to mitochondrial damage, and release of pro-apoptotic proteins from the mitochondrial intermembrane space. this activates initiator caspase -> executioner caspase

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8
Q

what families of proteins constitute the apoptotic machinery in mammalian cells?

A 
1- Bcl-2 protein family
2- caspases 
3- death receptor 
4- inhibitors of apoptosis proteins
5- mitochondria
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9
Q

what types of Bcl-2 proteins are there?

A

a - bcl-2 anti-apoptotic proteins
b - bcl-2 pro-apoptotic proteins
c- BH3 only pro-apoptotic proteins

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10
Q

how was Bcl-2 discovered?

A

discovered in b-cell lymphoma was a gene frequently translocated to the immunoglobulin locus in lymphomas, resulting in ectopic expression of these cancers

overexpression found to block apoptosis

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11
Q

what is the general structure of pro-survival proteins?

A

9 alpha helices which are separated into 4 separate domains, allow the protein to be anchored to membrane

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12
Q

what is the general structure of BH3-only (pro-apoptotic) proteins?

A

amphipathic helix roughly comprised of 9-16 amino acids

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13
Q

what is the structure of Bcl-XL?

A

hydrophobic a-helices in anti-parallel organisation

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14
Q

what is meant by the term: apoptotic switch/

A

the way in which pro-apoptotic proteins must bind to and inhibit the anti-apoptotic proteins before apoptosis can be induced

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15
Q

which two membrane proteins regulate the mitochondrial membrane permeability?

A

VDAC: voltage-dependent anion channel

adenosine nucleotide transporter

both of these form a complex that acts as a conductance channel

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16
Q

what is the significance of the mitochondrial intermembrane space in apoptosis?

A

the site where most pro-apoptotic mediators are present (cytochrome c)

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17
Q

what is the mPTP?

A

mitochondrial permeability transition pore

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18
Q

how is the mPTP activated?

A

pro-apoptotic initiator proteins bind BCl-xl and Bcl-2. activating pro-apoptotic functions. there is a sudden increase in permeability which causes the mPTP to be constitutively active, small molecules enter and increase osmolarity -> membrane bursts

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19
Q

how is Bax assembled in apoptotic mitochondria?

A

forms oligomers that assemble into arcs, rings and pores in mt membrane

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20
Q

what are caspases?

A

a family of cysteine, aspartate-specific proteases that cleave after aspartate residues in a DxxD motif

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21
Q

which caspases are initiators?

A

caspases 1,9,8, and 10

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22
Q

which caspases are executioners?

A

caspase 3, 6 and 7

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23
Q

what is the function of the tail in initiator caspases?

A

mediates protein-protein interactions

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24
Q

what is the difference between the initiator and executioner caspases?

A

the executioner caspases lack the pro-domain which is synthesised as a pro-enzyme

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25
Q

what is the unifying feature amongst all caspases?

A

all synthesised as inactive zymogens containing a pro-domain followed by large and small subunits - activated by cleavage of DXXD motifs at interfaces between subunits

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26
Q

what is meant by ‘the proximity-induced dimerisation model’?

A

initiator caspases must bring two pro-caspases into close proximity. there is trimerisation of receptor, bringing the death domain and fas-associated death domain together in close proximity. death effector domains dimerise, eventually forming the DISC

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27
Q

what is the ‘DISC’?

A

death induced signalling complex - site where pro-caspases are assembled

28
Q

what is apaf-1?

A

apoptotic protease activating factor-1

29
Q

what are the components of the apoptosome?

A

Apaf-1, caspase-9, cytochrome c, ATP

30
Q

outline formation of the apoptosome

A

1-cytochrome c binds specific domain of apaf1
2- ATP-ADP exchange -
3- dimerisation of pc-9 catalytic domains - bringing pro-caspase into proximity for cleavage to active caspase 9

31
Q

how are executioner caspases activated?

A

primary cleave at DXXD motif by initiator caspase, ssecondary cleavage

32
Q

what is the consensus cleavage site for caspase 3 (Rock1)?

A

DETD

33
Q

what are death receptors?

A

cell surface receptors that transmit apoptotic signals upon binding specific ligands, activating a caspase cascade within seconds of ligand binding

34
Q

what gene family do death receptors belong to?

A

tumour necrosis factor

35
Q

what are the best characterised death receptors?

A

CD95 (Fas)
TNFR1
TRAIL

36
Q

how were IAPs first discovered?

A

first discovered as virally-encoded proteins used by baculovirus as a strategy to suppress apoptosis of host cells

37
Q

what do IAPs do?

A

bind directly to caspases, inhibiting their activity

38
Q

what is a BIR domain?

A

required for binding to and inactivating caspases

39
Q

what is Smac?

A

second mitochondria derived activator of apoptosis

40
Q

what is Diablo?

A

direct IAP binding protein with low pI

41
Q

how can apoptosis be induced?

A

via extrinsic or intrinsic pathways

42
Q

how is apoptosis induced in the extrinsic pathway?

A

involves signals transduced from the outside of the cell via death receptors such as Fas, TNF-Rs, TRAIL

43
Q

how is apoptosis induced via the intrinsic pathway?

A
  • signals are induced from within cell

- as a result of exposure to damage inducing agent

44
Q

how might tumour cells evade apoptosis?

A

up regulation/overactivation of anti-apoptotic proteins

down regulation or inactivation of pro-apoptotic proteins

45
Q

which pathways are modified in apoptosis in the cancer cell?

A
  • loss of pro-apoptotic signals (e.g. LKB1)
  • increase in pro-survival signals e.g. Bcl-2
  • checkpoint defects (Loss of checkpoint 2)
  • loss of sensitivity to apoptotic signalling
  • mutations of DNA damage sensing systems
  • oncogene activation
46
Q

what is the importance of the mTOR kinase?

A

only pathway that integrates signals from growth factors and nutrients with levels of O2

47
Q

what is mTOR?

A

serine//threonine kinase; present as a complex of mTOR/mTOR2

48
Q

what processes does mTOR control?

A

cell growth/proliferation
angiogenesis
cell survival

49
Q

how is p53 regulated?

A

p53 and mdm2 form an auto regulated feedback loop. mdm2 is a transcriptional target of p53, when synthesised, it inhibits p53

50
Q

what is ATM?

A

a kinase that senses DNA damage - activation of these kinases leads to phosphorylation of p53, triggering tetramerisation

induces expression of a number of TFs

51
Q

what is the basis for B cell lymphoma?

A

translocation of antibody H chain enhancer on chromosome 14 to chromosome 18, where bcl-2 is located

52
Q

what advantage does the Bcl-2 translocation in B cell lymphoma offer?/

A

constitutive expression offers an advantage for tumour cell survival

53
Q

what is FLIP?

A

a decoy adapter protein for caspases - over expression is associated with cancer

54
Q

how do decoy receptors function to regulate apoptosis?

A

bind trail ligand, but do not activate pro-caspases. prevents apoptosis from becoming activated

55
Q

what is the difference between the death receptors and decoy receptors?

A

death receptors have a transmembrane region which recruits adaptors. decoy receptors may lack CTD or have a truncated CTD

56
Q

in which ways may the receptor and DISC be defective in cancer?

A

1- epigenetic silencing
2- receptor gene mutation
3- increased expression of decoy receptors
4- increased c-flip expression

57
Q

what are the 3 Ras genes?

A

N–Ras
Ha-Ras
Ki-Ras

58
Q

what is the most common mutation in K-Ras?

A

glycine-> valine mutation that suppresses the GTPase activity of the protein

59
Q

what is p10?

A

commonly mutated tumour suppressor that converts PIP3 back to PIP2

60
Q

why are mutations to PI3K common in cancer?

A

1-PI3K phosphorylates the membrane lipid PIP2
2- PIP3 recruits akt, which is phosphorylated at 2 specific residues
3- phosphorylation of pro-apoptotic BAD

mutation to PI3K prevents stimulation of BAD

61
Q

in PI3K signalling, which protein phosphorylates Akt?

A

mTOR

62
Q

what are the therapeutic strategies for targeting apoptosis?

A

1- inhibiting p53-mdm2 interaction
2- Bcl-2 family inhibitors
3-XIAP inhibitors
4- activation of the trail receptor

63
Q

what is the therapeutic advantage of mdm2 inhibitors??

A
  • increased levels of p53

- tumour suppressor

64
Q

how does the drug Nutlin 2 work?

A

mimics binding of p53 and mdm2 via specific residues on hydrophobic groove (L26, W23, F19)

65
Q

what are the effects of Nutlin 2 on cancer cells?

A
  • accumulation and activation of p53
  • cell cycle arrest in G1 and G2
  • inhibits growth of tumours in xenograft models without causing significant toxicity
  • cells with WT p53 have increased sensitivity to Nutlin 2
66
Q

what characterises inhibitor of apoptosis proteins (IAPs)?

A

presence of 1 or more BIR domains - which bind or inhibit caspases

67
Q

what is the domain structure of IAP proteins?

A

BIR domain - caspase binding domain
CARD domain
RING - e3 ubiquitin ligase catalyses transfer of ubiquitin to substrate bound by RING domain. promotes ubiquitinylation and degradation of IAPs and destruction of caspases

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