CE L3 Tumour suppressor genes

Question 1

Tumour suppressor genes normally function to

Answer 1

restrict growth

Question 2

Tumour suppressor genes are usually recessive or dominant?

Answer 2

recessive - you need mutations in both copies

Question 3

Oncogenes are recessive or dominant?

Answer 3

Dominant - only need mutation in one

Question 4

What sort of mutations in tumour suppressor genes predispose to cancer?

Answer 4

Loss of funciton

Question 5

Can you inherit mutations in tumour suppressor genes?

Answer 5

yes- so later in life you lose the second functioning copy.

Inherited predisposition as opposed to inherited disease

Question 6

Cancer tend to have at least 1 …………. mutation and 1 ………… mutation

Answer 6

1 or more tumour suppressor genes

1 or more oncogene

Question 7

…….. and ………… mutations result in no protein or protein with altered function

Answer 7

Deletions and point mutations

Mostly deletions as it causes frame shift

Question 8

6 classes of tumour supressor gene

Answer 8

Growth/development supressor
Cell cycle check point protein
Cell cycle inhibitors
Inducers of apoptosis
DNA repair enzymes
Developmental pathways

Question 9

2. e.g. of inhereted prdispostions

Answer 9

APC (part of Wnt pathway) - precancerours intestinal polyps

BRACA1 - 60% probability of breast cancer

Question 10

what leads to retinoblastoma?

Answer 10

loss of pRb

recessive trait

Question 11

How does pRb and p16 regulate the cel cycle

Answer 11

In G1 phase
Growth factor stimulation
Cyclin D1 levels rise
Cyclin D/CDK4 complex
CDK4 phosphorylates pRb
pRb releases E2F
E2F active

Question 12

Mutation on pRb has what effect on E2F?

Answer 12

E2F is free all the time to drive S phase and the cell through the cell cycle.

So you don’t need growth factor to drive the pathway

Question 13

What is E2F

Answer 13

a transcription factor

drives S phase

Question 14

What is usually the stimulous for E2F to drive the cell cycle

Answer 14

GF/cyclin D

(create a cyclin D/CDK4 complex

Question 15

What is usually the stimulus for E2F to drive the cell cycle

Answer 15

GF/cyclin D

create a cyclin D/CDK4 complex that phosphorylates pRb. pRb the resleases E2F

Question 16

What happens in a loss of function of p16?

Answer 16

removes the ability to halt the cell cycle in order to repair DNA

(mutations are passed on to daughter cells and accumulate)

Question 17

p53 is sometimes called

Answer 17

GUARDIAN OF THE GENOME

evolved to prevent cancer deveopment

Question 18

Where is p53 normally?

Answer 18

complexed to MDM2

Question 19

How is p53 released?

Answer 19

Stree signals inhibit MDM2 allwoing activation of p53

Question 20

p53 is active as a …… and has what function ……

Answer 20

transcriptional regulator

tetramer

Question 21

p53 is active as a …… and has what function ……

Answer 21

transcriptional regulator

tetramer - it is stabilised by biding to damaged DNA

Question 22

5 cellular responses to p53

Answer 22

Apoptosis
Differentiation
DNA repair
Senescence
Cell cycle arrest

Question 23

4 Stressos that activate p53 (by inhibiting MDM2 to which it is normally complexed)

Answer 23

DNA damage
Oncogenes
Loss of survival signals
Hypoxia

Question 24

p53 regualtes expression of (3)

Answer 24

p21 cyclin dependant kinase inhibitor - arrest
MDM2 - autoregulation
Bax - pro-apoptotic

Question 25

p53 inhibits cell growth through (2)

Answer 25

cell cycle arrest

induction of apoptosis

Question 26

Mutations in p53 occur in how many cancers

Answer 26

over 50%

Question 27

Why are mutant p53 problematic

Answer 27

• they are more stable (less liekly to be degraded)

- interfered with wildtype p53

Question 28

In what disorder is there inhereted mutation in p53

Answer 28

Li Fraumeni syndrome - predisposition to tumour formaiton

Question 29

How does mutated p53 interfere with wildtype?

Answer 29

It must bind as a tetrameter for transcription. If 1 of 4 is mutated no transcription occurs

Question 30

What enviromental factors lead to p53 mutation (2)

How?

Answer 30

1. Benzo(a) pyrine in cigarette smoke
2. Aflatoxin (fungal metablolite)

Both cause G>T transversion at suceptible regions of DNA

Question 31

What enviromental factors lead to p53 mutation (2)

How?

Answer 31

1. Benzo(a) pyrine in cigarette smoke
2. Aflatoxin (fungal metablolite)

Both cause G>T transversion at suceptible regions of DNA

Question 32

Majority of mutation hot spots in p53 are located in …………

Why is this a problem?

Answer 32

the DNA binding region - so it can still dimerise and do other things but not act as a TF

Question 33

Implications of p53 in cervical cancer

Answer 33

polymorphism increases susceptibility to HPV E6 mutation -

but its easier to just vacinate everyone

Question 34

Implications of p53 mutation in chemo

Answer 34

chemo damages DNA then relies on an active apoptotic pathway.

So it doesnt work as well with mutated p53. Restoring this function is a theraputic target.

Question 35

e.g. of p53 target therapy

Answer 35

ADVEXIN

-adenoviral transfer of p53 gene into tumour cells

appears to halt growth/shrink