Tumour suppressor genes

Question 1

Tumour suppressor genes normally function to promote growth or restrict growth?

Answer 1

Restrict Growth

Question 2

Do tumour suppressor genes cause cancer by gain of function or loss of function mutations?

Answer 2

Loss of function

Question 3

What are the main classes of tumour suppressor genes?

Answer 3

Growth/development suppressors e.g. TGFB, Patched I
Cell cycle checkpoint proteins e.g. pRb, p53
Cell cycle inhibitors e.g. CDK1, p16
Inducers of apoptosis e.g. Bax, p53
DNA repair enzymes e.g. Xeroderma pigmentosa
Developmental pathways e.g. patched (Hh pathway)

Question 4

How can hereditory predispositions cause cancer?

Answer 4

Inherit germ line mutation in allele

Subsequent somatic mutation in other

Question 5

If you have the BRCA1 gene what is your probability of inheriting breast cancer?

Answer 5

60%

Question 6

What is retinoblastoma?

Answer 6

Tumours in the retina

Question 7

What percentage of retinoblastoma cases are inherited?

Answer 7

40%

Question 8

What contributes to the growth of retinoblastoma?

Answer 8

Loss of function of pRb

Question 9

What happens in G1 phase of the cell cycle?

Answer 9

Getting ready for copying the DNA in S phase. Check whether the cell is healthy enough to go through mitosis.

Question 10

What drives Cyclin D?

Answer 10

Growth factor which goes through Ras-MAPK oathway and increases transcription factor AP-1

Question 11

What does Cyclin D complex with to phosphorylate pRb?

Answer 11

CDK4

Question 12

What happens once pRb has been phosphorylated?

Answer 12

pRb changes its conformation and lets go of E2F

Question 13

What is E2F?

Answer 13

A transcription facotor

Question 14

What does E2F do?

Answer 14

Drives the transcription of genes required for S phase to copy the DNA

Question 15

What happens if there is no pRb?

Answer 15

There is nothing to bind and sequest E2F, so it is active all of the time. Even without nay growth factor binding to receptors, the pathway is constitutively active and the cells grow faster.

Question 16

What happens with loss of function of p16?

Answer 16

it removes the ability of a cell to halt the cell cycle in order to repair damaged DNA. Mutations are passed onto daughter cells and accumulate.

Question 17

what is p53?

Answer 17

a transcription factor

Question 18

What did p53 evolve to do?

Answer 18

Prevent tumour development

Question 19

How is p53 found in cells?

Answer 19

Present at low levels, complexed to an inhibitor protein MDM2.

Question 20

What inhibits MDM2 and allows activation of p53?

Answer 20

Stress signals (bacterial infection or UV radiation)

Question 21

How many molecules of p53 are required to complex to make one transcription factor complex?

Answer 21

4

Question 22

What happens if one molecule of p53 is non-functional in the tetramer?

Answer 22

The whole lot doesn’t work

Question 23

When is p53 upregulated?

Answer 23

When we cause environmental damage to our DNA

Question 24

What types of stress can cause upregulation of p53?

Answer 24

DNA damage
Ocnogenes
Loss of survival signals
Hypoxia

Question 25

What responses can p53 cause to environmental damage?

Answer 25

``` Cell cycle arrest Differentiation DNA repair Apoptosis Senescence ```

Question 26

Why does p53 cause differentiation after environmental damage?

Answer 26

Pushing the cells towards differentiation will cause their growth to go down because they are becoming more specialised

Question 27

When does p53 cause senescence?

Answer 27

If DNA repair doesn't work, it will put the cells into a stasis where the cells are alive but they don't really do anything

Question 28

When does p53 cause apoptosis?

Answer 28

Mainly what happens when the DNA can't be repaired

Question 29

p53 regulates the expression of what?

Answer 29

p21 cyclin dependent kinase inhibitor-arrest MDM2 (inhibitor of p53 action)-autoregulation Bax-pro-apoptotic protein

Question 30

Mutations in p53 occur in what percentage of cancers?

Answer 30

>50%

Question 31

Are mutant p53 proteins more stable or unstable?

Answer 31

Stable (but not functional so not really doing any good)

Question 32

Mutations in p53 commonly occur where?

Answer 32

In the DNA binding region

Question 33

What is Li Fraumens Syndrome?

Answer 33

Inherited mutated p53. Childhood tumours and usually early death

Question 34

What is p53 inactivated by?

Answer 34

Carcinogens

Question 35

What percentage of human lung cancers have mutations in p53?

Answer 35

60%

Question 36

What chemical in cigarette smoke is metabolised in the liver generating a potent mutagen?

Answer 36

Benzo(a)pyrine

Question 37

The mutagen in cigarette smoke causes transversions from what to what?

Answer 37

G-->T in DNA

Question 38

What can HPV do to p53?

Answer 38

Binds to p53 binding region and stops it from tetramising (E6 subunit) and prevents its ability to bind to DNA and act as a transcription factor.

Question 39

Is p53 rarely or commonly mutated in cervical cancer?

Answer 39

Rarely

Question 40

What affects the susceptibility to HPV E6 mediated degradation?

Answer 40

Polymorphisms

Question 41

What do chemo agents and radiation rely on for their cytotoxic effects?

Answer 41

p53 for apoptosis which normal cells have

Question 42

What often makes tumour cells resistant through lack of functional apoptotic pathway?

Answer 42

Lack of p53

Question 43

What is going to happen over time to people without p53?

Answer 43

Gradual accumulation of damage and mutations

Question 44

What does Advexin do?

Answer 44

Adenoviral transfer of p53 gene into tumours

Question 45

Advexin was FDA fast tracked for what?

Answer 45

Head and neck cancers

Question 46

What does advexin appear to do?

Answer 46

Halt growth and shrink tumour size

Question 47

How is Advexin administered?

Answer 47

Directly into tumours

Question 48

How many deaths have been attributed to Advexin therapy?

Answer 48

None