Resistance to cell death Flashcards

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1
Q

what affects the net number of cells in the body

A

balance between cell growth and apoptosis

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2
Q

what enzymes are the key players in apoptosis?

A

caspases

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3
Q

what does caspaces catalyse?

A

proteolysis to help breakdown cellular components for disposal

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4
Q

what does defects in apoptosis influence the effectiveness of?

A

the drugs which exert their effect by inducing apoptosis

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5
Q

external induction of apoptosis

A

by death factors

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6
Q

internal inducers of apoptosis

A

physical or chemical insults such as DNA damage or oxidative stress

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7
Q

which two pathways can be activated to cause apoptosis?

A

extrinsic

intrinsic

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8
Q

caspases work by cleaving where on proteins?

A

proteolysis at aspartate residues

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9
Q

TF: caspases are central to the intrinsic pathways only

A

false

central in both

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10
Q

how many mammalian caspases have been identified so far?

A

13

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11
Q

how are caspases synthesised?

A

as inactive enzymes called procaspases

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12
Q

how do procaspases get activated

A

by cleavage at aspartate residues

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13
Q

what are the class of receptors on the cell membrane which are related to apoptosis called?

A

death receptors

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14
Q

examples of death factors and their ligands

A

Fas ligand- Fas receptor

tumour necrosis factor ligand - TNF receptor

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15
Q

how is TNF found compared to Fas ligand

A

TNF is a soluble factor

Fas ligand is bound to the plasma membrane of neighbouring cells

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16
Q

what happens firstly when ligands bind to the death receptor son cells?

A

the receptor undergoes a conformational change and oligomerize in order to transduce the signal
the conformational change exposes the death domains on the cytoplamsmic tail
this enables intracellular adapter proteins such as FADD and TRADD to bind to their death domains.

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17
Q

where are death domains located on the death receptor?

A

cytoplasmic tail

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18
Q

when the death domains are exposed which proteins can then bind to these domains?

A

FADD and TRADD

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19
Q

what does FADD and TRADD stand for

A

Fas associated death domain protein

TNF Receptor associated death domain protein

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20
Q

what do these FADD and TRADD proteins do when they bind to the death domain on the cytoplasmic tail on the recepot?

A

transduce the death signal from the receptor to the caspases.
they recruit procaspase 8 which when in close proximity of other procaspase 8 will become activated by self cleavage

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21
Q

how do procaspase 8 become activated once recruited to the death domains by TRADD and FADD?

A

when they come in close proximity of each other they activate by self cleavage

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22
Q

what is this combination of death ligands, receptor adaptors (FADD and TRADD) and imitator caspases called?

A

death inducing signalling complex or DISC

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23
Q

once caspase 8 is produced what happens?

A

they activate other procaspases which are called executioner caspaces

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24
Q

what numbers are the caspases known as executioner caspases?

A

3,6,7

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25
Q

what does this whole extrinsic pathway result in once caspases 3,6 and 7 are produced by caspase 8 ?

A

proteolysis of target proteins

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26
Q

target proteins of caspases 3,6 and 7 in the extrinsic pathway?

A
nuclear lamins 
cytoskeletal proteins 
structure 
kinases 
enzymes
27
Q

what do targeting nuclear lamins result in?

A

nuclear shrinkage

28
Q

which cytoskeletal proteins get targeted by caspases 3,6 and 7? effect?

A

actin

allow for cell rearrangement

29
Q

what triggers the intrinsic pathway?

A

DNA damage and oxidative stress

30
Q

which family of proteins are activated in DNA damage and oxidative stress in the intrinsic pathway? where are they located?

A

bcl-2

outer membrane of the mitochondria

31
Q

properties of the bcl 2 family? number of members?

A

25 members
mediates protein protein interactions
forms homodimeric or heterodimeric complexes

32
Q

anti-apoptotic members of the bcl-2 family share sequence similarity across which domains?

A

BH1-4

33
Q

what happens if these antis-apoptotic members of the bcl-2 family (BH1-4) are over expressed

A

resistance to apoptosis

34
Q

what family of proteins are Bid, Bim and Bad apart of?

A

BCL-2

35
Q

effect of Bid, bim and bad on apoptosis

A

bid and bim : can induce apoptosis directly

bad: sensitise to activation of apoptotic program when stress signal is present

36
Q

what does the inter membrane space of mitochondria supply to help apoptosis?

A

apoptotic mediators

37
Q

what regulates the release of apoptotic mediators from the mitochondrial inter membrane space? what is this process called?

A

proapoptotic bcl-2 members

mitochondrial outer membrane permeabilisation

38
Q

what is mitochondrial outer membrane permeabilisation?

A

proapoptotic bcl-2 members mediators regulate the release of apoptotic mediators from the mitochondrial inter membrane space

39
Q

what are the BH3 only proteins in the bcl 2 family??

A

Bid and Bim and bad

40
Q

what domains does Bax have?

A

multi domain

41
Q

what happens regarding Bid, Bim and Bax once activated by an apoptotic signal?

A

BH3 only proteins Bid and Bim bind to and activate Bax.
this causes a conformational change in Bax and it translocates from the cytoplasm to the mitochondria and inserts itself into the outer mitochondrial membrane

42
Q

what happens to Bax when its activated by BH3 only proteins Bid and Bim?

A

it undergoes conformational change and translocates from the cytoplasm to the mitochondrial outer membrane

43
Q

what happened once Bax translocates into the outer mitochondrial membrane?

A

oligomerization of molecules which increases the permeability of the outer membranes by forming chandelles which allows the release of apoptotic mediators

44
Q

what is XIAP and what does it do in relation to apoptosis?

A

STOP APOPTOSIS: X chromosome linked inhibitor of apoptotic proteins
binds directly to and inhibits the activity of caspase 3 and 7 (executioner) after they have been processed by binding to their active site.and inhibits caspase 9 by disrupting the active site

45
Q

besides inhibitors of apoptotic proteins, what else mediates apoptosis? how?

A

Smac- second mitochondria derived activator

inhibits IAPs

46
Q

how does p53 effect apoptosis

A

induces

47
Q

2 means by which p53 induces apoptosis?

A

transcription dependent and transcription independent means

48
Q

how does p53 induce apoptosis by acting as a Transcription factor?

A

induces expression of genes encoding for death and pro apoptotic members of the bcl-2 family

49
Q

examples of genes which p53 upregulates when acting as a transcription factor?

A

Fas receptors Bax and Bak

50
Q

examples of factors which p53 reduces the expression of when acting as a transcription factor for apoptosis

A

anti apoptotic factors such as:

bcl-2 and bcl-cl and IAPs

51
Q

example of how p53 can exert transcription independent regulation of apoptosis

A

activation of Bax in the cytoplasm and subsequent caspase activation

52
Q

how can p53 also alter the net functional balance of the bcl-2 family of proteins?

A

by releasing Bid from sequestration by antiapoptotic proteins such as the Bcl-xL

53
Q

what is puma and what is it a target of?

A

p53 unregulated modulator of apoptosis

p53 target essential for apoptosis induced by p53

54
Q

what does p53 do to puma and what is the results of this (regarding Bcl-xL and Bak)

A

p53 activates transcription of Puma which then acts to release P53 from bcl-xl in the cytoplasm so that p53 can directly activate Bak

55
Q

what is essential to the development of cancer regarding apoptosis

A

inactivation of apoptosis

56
Q

what can happen to treatment in tumours where apoptosis is not the main mechanism for cell death?

A

resistance to treatment

57
Q

how can inactivation of p53 help cancer cells evade cell death?

A

reduces the overall level of cell death

58
Q

what happens in cells of epithelial origin which do not primarily undergo apoptosis if p53 is lost?

A

no change in level of cell death

other pathways induce cell death

59
Q

2 ways to target caspases for therapy?

A
  1. inhibit anti-apoptotic members of the family

3. induce the expression of proapoptotic members of the bcl-2 family

60
Q

what drug types can be used to target caspases to promote apoptosis ?

A

IAP inhibitors

Smac peptides

61
Q

what is a common feature of all IAPs regarding a repeat on amino acids? what can this be targeted by ? what will this achieve

A

presence of baculovirus IAP repeat on approximately 70 amino acid domains
small molecules to achieve selective activation of caspases

62
Q

what does ABT737 inhibit?

what is it classed as?

A

Bcl-2, Bcl-xL and bcl

BH3 mimetic small molecule inhibitors

63
Q

does ABT737 directly induce apoptosis

A

no it enhances death signals