Brainscape's Knowledge GenomeTM

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


See full index

cancer > 8. p53 > Flashcards

8. p53 Flashcards

1
Q

what can cause DNA damage?

A
  • exposure to mutagens
  • oxidative damage
  • radiation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what types of genetic lesions can be made?

A

double strand breaks, single strand breaks, base changes, translocations, amplifications

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

what do we not want to tolerate and why?

A

DNA damage as it leads to the accumulation of changes in DNA
and these can lead to cancerous mutations

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

what enzymes keeps ROS low in cells and how does this differ between people

A

cytochrome oxidase I

individuals have different alleles of this which make them better or worse at removing ROS

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

can RO S be tolerated in low levels

A

yes

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

what happens if cytochrome oxidase is mutated?

A

can lead to accumulation of ROS and thus accumulation of DNA damage
>mutations in CO1 are associated with increased risk of cancer

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

name a group of inherited skin disorders which is characterised by UV sensitivity

A

Xeroderma Pigmentosum

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

what happens to the DNA of people suffering from Xeroderma Pigmentosum and what implications does this have?

A

low levels of UV light causes DNA damage

>they are more susceptible to skin cancer

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

what genes are associated with Xeroderma Pigmentosum?

A

there are 7 genes associated with this disease and they are all involved in nucleotide excision repair which is essential for damage made by UV

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

what is a karyotype test and how might this vary between normal cells and cancer cells?

A

test to identify and evaluate size, shape and number of chromosomes in cells
>probes specific to chromosomes for hybridisation
>cancer cells are aneuploidy - most chromosomes are present in three copies
> large chromosomal translocations
>within chromosomes - deletions, translocations and point mutations.

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

when cancer genomes are sequenced and compared to normal genomes, what is hard to say about these mutations?

A

which mutations are driving the cancer and which are just bystander mutations

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

what are bystander mutations?

A

these are mutations which are brought about by random chance and don’t really contribute to the disease

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

what are drive mutations?

A

> occur statistically at a greater frequency than would be expected for a standard background mutation
this implies they have been selected for as the disease causing mutations

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

what does DNA repair ensure?

A

we don’t accumulate mutations at rates that we should not

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

what are the four responses a cell could have to DNA damage?

A
  • repair and return to normal
  • cell death (cell can be replaced)
  • senescence
  • mutations - the above responses are all trying to prevent this
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

how was p53 identified?

A

identified by doing screens for genes that are changed in cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

name the disease where p53 was also found to be mutated and is an early onset cancer prone syndrome? how common is this? and why does this happen?

A

Li-Fraumeni Syndrome
>affects 100 families world wide
>mutation of TS leads to elevated levels of DNA damage - individuals cells are hypersensitive to DNA damage

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

what does positional cloning do and show and why was this hard in Li-Fraumeni Syndrome

A

> genomic mapping protocol that identified p53
obtained genomic DNA from affected and unaffected people
look for mutations that are common to affected and not common to in-affected people
indeify candidate gene
not many people as they die young and don’t reproduce

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

what small DNA viral transforming proteins interact with p53?

A

HPV E6, SV40 T antigen and Adenovirus E1B

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

p53 is a tumour suppressor, how is the active species found?

A

as a homo-tertramer

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

describe the body plan of p53?

A

TA domain
DNA binding domains
tetramer formation domain

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

what happens when p53 is KO in mice? and what does this show?

A

they are caner prone, significant reduced survival

>the importance of p53 is to maintain a stable genome and prevent cancer.

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

what is seen when mice are give an extra p5 and exposed to mutagen?

A

they are even more resistant to cancer

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

animals like elephants have more cells than us, there cells have been through more divisions but they hardly ever get cancer, why is this?

A

they have 20 copies of the p53 gene in their genome

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

give a potential use of genome engineering

A

give people are additional p53 so that they will be less cancer prone.

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

what is the frequency of p53 mutation in cervical cancer and why is this?

A

6%

HPV inactivates p53 and so does not require mutations to lose its function

27
Q

why are people that have mutated p53 likely to develop cancer?

A

they can accumulate further mutations which lead to the disease

28
Q

what type of mutations are normally found in p53? and where are they?

A

missense mutations, there are point mutations in which a single nucleotide change results in a code that codes for a different amino acid

29
Q

when mapped back to the 3D structure of the proteins where are these mutation hotspots in p53?

A

mostly in the DNA binding domain - surface residues that specifically interact with DNA targets of p53, meaning that they can no longer specifically bind and modulate gene expression

30
Q

what affect can other mutations have on p53, in addition to directly affecting DNA binding site?

A

can effect how the protein folds and retains its structure. this has implications on how p53 functions and binds target genes.

31
Q

if you are heterozygous for p53, you would expect to have half WT activity? TRUE or FALSE?

A

false, you will have less than half WT activity

32
Q

what implication does p53 being a tetramer have on binding specificity?

A

the four subunits give DNA binding specificity

33
Q

when will mutant p53 still be incorporated into tetramer?

A

when the mutations is in the DNA binding site and so does not affect the overall folding of the proteins and the tetramer forming domain

34
Q

what happens if a mutant p53 is incorporated into the tetramer?

A

this will compromise the ability to bind DNA - lowers the affinity of binding

35
Q

why are p53 mutations in the DNA binding domain dominant negatives?

A

functionally it dominates the wild type version

36
Q

when mutations arise in p53 that affect its folding what happens?

A

are directed to be degraded and so these is loss of p53 activity due to reduced p53

37
Q

define the consensus sequence of p53?

A

two degenerate sequences that are separated by 0-2bps - this means that they are found in many places in the genome

38
Q

bioinformatics identified 524 target sequences of p53, how accurate is this likely to be?

A

probably no way near as many target genes as are actually affected
>because they way we do bioinformatics excludes quite a lot of the things that are targeted

39
Q

what are the three classes of genes that p53 binds?

A
  • arrest and repair
  • apoptosis
  • regulators
40
Q

what do arrest and repair genes do?

A

block the cell cycle, allow for repair to take place and then allow the cell cycle to recommence.

41
Q

give an example of a target p53 genes that causes cells cycle arrest? and what types of arrest does this cause?

A

p21 - a cdk inhibitor

this causes G1 phase arrest

42
Q

p21 can block cell cycle, what else can it do?

A

bind PCNA

43
Q

what does PCNA stand for?

A

proliferating cell nuclear antigen

44
Q

where is PCNA seen?

A

in the nucleus of proliferating cells

45
Q

how does PCNA bind DNA?

A

as a homotrimer

>there is a hole through the middle that accommodates DNA

46
Q

what is PCNA function?

A

it acts as a sliding clamp that which functions as a processivity factor of DNA polymerase - its helps DNAP speed along the DNA when replicating

47
Q

when p21 binds PCNA what does this favour?

A

p21 binding blocks DNA polymerase binding and processivity

>favouring short repair type DNA synthesis

48
Q

what does PCNA binding impose?

A

an S phase block

49
Q

where can p21 impose cell cycle arrest and what does this depend on?

A

G1 phase and S phase

this depends on what phase the DNA damage even occurs

50
Q

name a non-protein target of p53? and what does this do?

A

miRNA
>this regulates the translation of key cell cycle components
>can down regulate cdk4 and cyclin E translation
>this can impose a G1 block

51
Q

name the target proteins for p53 that is implicated in G2/M phase arrest? and what do they bind?

A

14-3-3 proteins

>they bind phospho-serine containing peptides

52
Q

where is 14-3-3 when not bound it a ligand?

A

in the nucleus

53
Q

what happens when the cell cycle is commencing in terms of G2/M phase?

A

cdc25 is functional and dephosphorylates cdk1

54
Q

what kinase is activate when there is DNA damage and what does this P to prevent G2/M phase transition?

A

Chk1
>this P cdc25 at a serine residue
>this becomes a ligand for 14-3-3
>this binding results in 14-3-3 nuclear export of cdc25
>it cannot remove P from cdk1 and so cdk1 remains inhibited

55
Q

which are the two main transcription targets of p53 in terms of apoptosis? and what are they?

A

Bcl2 - anti-apoptotic repressed by p53

Bax - pro-apoptotic activated by p53

56
Q

how is apoptosis triggered?

A

> Bcl2 stabilises outer mit membrane
cyt c between membranes for oxidative P
increase in Bax/reduction in Bcl2 results in cyt C is released and binds adaptor proteins
this binds inactive pro-caspases
apoptosome is formed and cleaving process commences

57
Q

how do bcl2 and bax contribute to apoptosis?

A

> both have TM domains that localise them to outer membrane
Bax multimerising to form pore and let cyt c out
Bcl2 inhibits this pore formation
when there is more bax than bcl2 can inhibit there is greater changes of cyt c release

58
Q

name another target genes of p53 that regulates cells death, and how does it do it?

A

PTEN

59
Q

Akt is a pro-survival, pro-proliferative kinase what can it P to prevent cell death? and what regulates Akt?

A

pro-caspases to stop them being active
>PTEN inactivates Akt through negative regulation on PIP3
>this allows pro-caspases to be active

60
Q

what is Bad? and what does it do?

A

a protein that promotes apoptosis

>it competes of binding of Bcl2 so that it can not for heterodimer with Bax

61
Q

how can Akt affect bad?

A

P it and prevent it from interacting with out mit membrane - this prevents apoptosis

62
Q

name three substrates of Akt?

A
  • pro-caspases
  • bad
  • MDM2
63
Q

what is MDM2?

A

E3 ubiquitin-protein ligase that mediated ubiquitination of p53 and tags it for degradation

64
Q

by promoting MDM2, what affect does Akt have? and what happen when Akt is inactive?

A
  • promotes degradation of p53
  • prevents cell cycle arrest and apoptosis
    >when Akt is inactive, MDM2 is inactive

cancer (24 decks)

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