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Cancer Biology > Tumour Suppressors > Flashcards

Tumour Suppressors Flashcards

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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

Study These Flashcards
A

Maspin
TSP1
PAI1
GD-AIF

22
Q

Genes produced and inhibited by p53 involving metabolism

Study These Flashcards
A

Inhibit G6PDH
Inhibit PGM
Sestrins
TIGAR

23
Q

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

Study These Flashcards
A

Activates p21 which inhibits Cyclin/CDK

24
Q

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

Study These Flashcards
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
What is the warburg effect?
That most cancer cells produce energy through high rate glycolysis, followed by lactic acid fermentation in the cytosol
26
Name 3 pathways involved in the activation of p53
Arf pathway DNA damage pathways Nutlin
27
Name some stresses which activate p53
``` Telomere erosion DNA strand breaks UV radiation Transcriptional failure ROS Ribosomal stress Nutrient deprivation Viral infection Oncogenes Hypoxia Mitotic catastrophe ```
28
How does Mdm2 and p53 work in a negative feedback loop?
Increase Mdm2 -> ubiquitylate and target p53 for degradation Increase p53 -> stimulates transcription of Mdm2
29
What is etoposide?
A chemotherapy drug | causes DNA damage and activates p53 and increases its expression
30
What is nutlin?
A drug which induces p53 without DNA damage | Blocks the interaction between Mdm2 and p53
31
How does p53 stop being to Mdm2 and bind to p300 instead?
Through phosphorylation of p53
32
How does the ARF pathway promote p53?
Oncogenes stimulate ARF production -> ARF inhibits Mdm2 and p53 binding
33
What is the phenotype of p53 KO mice?
They grow to adulthood normally but are more susceptible to cancer
34
What is the phenotype of Mdm2 KO mice?
They die in utero at day 5
35
What is the phenotype of p53 and Mdm2 KO mice?
They are viable but get cancer | Indistinguishable from p53 KO mice
36
Why do Mdm2 KO mice die in utero?
Since there is too much p53 and therefore there is uncontrolled apoptosis
37
What is the most common p53 mutation?
Missense (>75%) - gain of function
38
Phenotype of p53 oncogenes
They increase metastatic potential and invasiveness | They are resistant to killing
39
How do p53 mutants become oncogenes?
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
What transcriptional proteins does mutant p53 bind to and what does it cause?
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
How do pathologists detect that p53 and mp53 is accumulating?
The increase in MDM2 since it doesn't bind to p53
42
Apart from mutation, how else can you get mp53?
Inactivate ARF and ATM
43
How does HPV induce cervical cancer?
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
What is the issue with p53 based drugs?
Effects normal cells - genotoxic effects
45
Name an p53 based therapy and what cancer it targets
Gendicine | Head and neck squamous cell carcinoma
46
How does gendicine work?
Triggers apoptosis
47
What is the effectiveness of gendicine?
64% of patients shows complete regression after 8 weeks of the drug in combination with radiotherapy
48
Name 4 drugs which restore p53 activity
Nutlin-3 PRIMA-1 RITA PhiKan083
49
Describe Nutlin-3
competitive inhibitor of p53, it binds to Mdm2 | No genotoxicity
50
What does PRIMA-1 do?
Restores mp53 through altering the covalent modifications
51
What does RITA do?
Binds to p53 and blocks the interaction with Mdm2
52
what does PhiKan083 do?
Binds to p53 Y220C mutant

Cancer Biology (13 decks)

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