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Cancer Biology > Tumour Suppressors > Flashcards

Tumour Suppressors Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

What is haploinsufficiency?

A

Loss of one copy of a gene is sufficient to permit the development of the disease

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2
Q

What cell cycle checkpoint is Rb present at?

A

G1/S phase

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3
Q

What cell cycle checkpoint is p53 present at?

A

G1/S phase
S phase
G2/M phase

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4
Q

What is the function of Rb?

A

To block E2F-DP1 complex and therefore inhibitors transcription of genes required for DNA synthesis

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5
Q

What cyclin does the MAPK signalling family produce?

A

Cyclin D1

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6
Q

In terms of Rb, what is the function of cyclin D1?

A

It phosphorylates it which inhibits its function

Acts as an oncogene

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7
Q

Name the domains of p53

A 
Transcription transactivating domain (TAD) -1 and 2 
DNA binding domain 
Tetramerisation domain (TET) 
Regulatory domain (Reg)
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8
Q

How often is p53 mutated in cancer?

A

~50% of the time

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9
Q

What are the 2 main mutational hotspots of p53 and which domain are they in?

A

273 and 248

DNA binding domain

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10
Q

How does p53 normally bind to the promoter?

A

As a tetramer

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11
Q

What is p300?

A

Histone acetyl transferases

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12
Q

What p53 domains bind to p300?

A

TAD

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13
Q

What are the subunits of p300?

A

Taz1
KIX
Taz2
IBiD

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14
Q

What does p300 induce?

A

acetylation of histones and transcription

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15
Q

What does p53 induce?

A 
Apoptosis
Growth arrest 
Repair 
Metabolism 
Angiogenesis block
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16
Q

How is p53 auto-regulated?

A

By inhibition by Mdm2, causing it to be targeted for degradation by the proteasome, to make sure it is at low levels until required

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17
Q

What is MDM2?

A

an E3 ubiquitin ligase

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18
Q

Genes produced by p53 involving growth arrest

A

p21
GADD45
14-3-3sigma
Reprimo

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19
Q

Genes produced by p53 involving apoptosis

A 
PIDD
Bax 
Fas 
PIG3 
KILLER
p53 AIP1 
PERP 
NOXA 
Scotin
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20
Q

Genes produced by p53 involving repair

A

p53R2

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21
Q

Genes produced by p53 involving angiogenesis block

A

Maspin
TSP1
PAI1
GD-AIF

22
Q

Genes produced and inhibited by p53 involving metabolism

A

Inhibit G6PDH
Inhibit PGM
Sestrins
TIGAR

23
Q

How does p53 inhibit the cell cycle at G1/S?

A

Activates p21 which inhibits Cyclin/CDK

24
Q

How does p53 inhibit the cell cycle at G2/M?

A 
It inhibits genes which normally cause the movement through the cell cycle : 
- CDC25C 
- Cyclin B1 
- CKS1 
- CDC2 
- Topo II 
- PLK1
It activates genes which inhibit the cell cycle:
- p21 
- GADD45 
- 14-3-3 sigma 
- Reprimo
25
Q

What is the warburg effect?

A

That most cancer cells produce energy through high rate glycolysis, followed by lactic acid fermentation in the cytosol

26
Q

Name 3 pathways involved in the activation of p53

A

Arf pathway
DNA damage pathways
Nutlin

27
Q

Name some stresses which activate p53

A 
Telomere erosion 
DNA strand breaks 
UV radiation 
Transcriptional failure 
ROS 
Ribosomal stress 
Nutrient deprivation 
Viral infection 
Oncogenes 
Hypoxia 
Mitotic catastrophe
28
Q

How does Mdm2 and p53 work in a negative feedback loop?

A

Increase Mdm2 -> ubiquitylate and target p53 for degradation
Increase p53 -> stimulates transcription of Mdm2

29
Q

What is etoposide?

A

A chemotherapy drug

causes DNA damage and activates p53 and increases its expression

30
Q

What is nutlin?

A

A drug which induces p53 without DNA damage

Blocks the interaction between Mdm2 and p53

31
Q

How does p53 stop being to Mdm2 and bind to p300 instead?

A

Through phosphorylation of p53

32
Q

How does the ARF pathway promote p53?

A

Oncogenes stimulate ARF production -> ARF inhibits Mdm2 and p53 binding

33
Q

What is the phenotype of p53 KO mice?

A

They grow to adulthood normally but are more susceptible to cancer

34
Q

What is the phenotype of Mdm2 KO mice?

A

They die in utero at day 5

35
Q

What is the phenotype of p53 and Mdm2 KO mice?

A

They are viable but get cancer

Indistinguishable from p53 KO mice

36
Q

Why do Mdm2 KO mice die in utero?

A

Since there is too much p53 and therefore there is uncontrolled apoptosis

37
Q

What is the most common p53 mutation?

A

Missense (>75%) - gain of function

38
Q

Phenotype of p53 oncogenes

A

They increase metastatic potential and invasiveness

They are resistant to killing

39
Q

How do p53 mutants become oncogenes?

A

Missense mutations in the DNA binding domain so instead of binding to p21, they bind close to promoters which drive the cell cycle through undergoing a conformational change

40
Q

What transcriptional proteins does mutant p53 bind to and what does it cause?

A

Ets2 - metastasis
NF-Y - proliferation
Mre11 - inhibits ATM-mediated DNA repair
NF-kappaB - Inflammation
MLL1 and MLL2 (methyltransferases) and MOZ (acetyltransferases) - chromatin re-modelling

41
Q

How do pathologists detect that p53 and mp53 is accumulating?

A

The increase in MDM2 since it doesn’t bind to p53

42
Q

Apart from mutation, how else can you get mp53?

A

Inactivate ARF and ATM

43
Q

How does HPV induce cervical cancer?

A

The E7 protein will inhibit p53 binding to the E2F-DP1 complex, causing hyperproliferation, which would normally produce ARF and cause p53-mediated apoptosis. However, p53 is inhibited by an E6 uquitin ligase and therefore p53 is degraded instead promoting apoptosis

44
Q

What is the issue with p53 based drugs?

A

Effects normal cells - genotoxic effects

45
Q

Name an p53 based therapy and what cancer it targets

A

Gendicine

Head and neck squamous cell carcinoma

46
Q

How does gendicine work?

A

Triggers apoptosis

47
Q

What is the effectiveness of gendicine?

A

64% of patients shows complete regression after 8 weeks of the drug in combination with radiotherapy

48
Q

Name 4 drugs which restore p53 activity

A

Nutlin-3
PRIMA-1
RITA
PhiKan083

49
Q

Describe Nutlin-3

A

competitive inhibitor of p53, it binds to Mdm2

No genotoxicity

50
Q

What does PRIMA-1 do?

A

Restores mp53 through altering the covalent modifications

51
Q

What does RITA do?

A

Binds to p53 and blocks the interaction with Mdm2

52
Q

what does PhiKan083 do?

A

Binds to p53 Y220C mutant

Cancer Biology (13 decks)

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