Evasion of growth suppressors

Question 1

Tumour supressor genes encode what?

Answer 1

proteins which inhibit cell proliferation

Question 2

what can happen to TSGs to allow cells to divid uncontrollably

Answer 2

loss

Question 3

TSGs need to be inactivated where to change the phenotype of the cell?

Answer 3

in both alleles

Question 4

TF: an individual carrying mutations in tumour suppressor genes in one allele will develop cancer.

Answer 4

false must be in both

Question 5

functions of TSGs? (3)

Answer 5

inhibit oncogene activation
prevent intracellular signalling
induce expression of genes to slow proliferation or cause cell death

Question 6

pRb is what? what happens to it in several cancers

Answer 6

tumour suppressor protein

dysfunctional in several cancers

Question 7

how does pRb prevent excessive cell growth?

Answer 7

prevents cycle progression by binding E2F

Question 8

What type of phosphorylation do we want on the pRb protein? why?

Answer 8

HYPO- phosphorylated

this is the state it must be in to bind E2F

Question 9

What happens to pRb (and by what) in cancer development?

Answer 9

phosphorylation by cyclin/ cyclin dependent kinases
results in dissociation of E2F and pRb
enables E2F transcriptional activity

Question 10

which viruses can inactivate pRb and lead to cancer?

Answer 10

HPV, adenovirus, simian virus

Question 11

E2F is a family which encodes for what?

Answer 11

family of genes that codifies transcription factors

Question 12

why is E2F important for DNA synthesis and hence needed for replication?

Answer 12

targets include DHFR enzymes needed for synthesis of purines A and G

Question 13

E2F induces expression of genes involved in? examples? what does this mean?

Answer 13

apoptosis
caspases 3,7,8
also induces cell death

Question 14

TF: E2F has only oncogenic characteristics?

Answer 14

false it stimulates DNA synthesis AND cell death

Question 15

what determines if E2F is going to function as an oncogene or TSG?

Answer 15

microenvironment conditions

Question 16

what is p53

Answer 16

a TSG

Question 17

what can happen to the p53 gene to make you PREDISPOSED to cancer?

Answer 17

inherit only one functional copy of the p53 gene from parents

Question 18

if you inherit only one functional copy of the p53 gene, what do we normally see in early life?

Answer 18

several independent tumours in different tissues

Question 19

___% of cancer patients have been shown to carry mutations in the p53 TSG.

Answer 19

60

Question 20

Examples of signals which activate p53? (4)

Answer 20

lack of nucleotides
UV, ionising radiation
hypoxia
transcription blockage

Question 21

once p53 has been activate what does it act as?

Answer 21

it functions as a TF and binds to DNA to express genes which STOP cell proliferation

Question 22

example of one of the genes activated p52 acts as a TF towards

Answer 22

p21- a cyclin/ cdk Inhibitor

Question 23

p21 is a?

Answer 23

cyclin/cdk inhibitor

Question 24

what happens in mutated p53

Answer 24

can no longer bind to DNA and therefore p21 isn’t produced and there’s no ‘stop’ signals for cell proliferation
uncontrolled cell growth

Question 25

besides cell cycle arrest, what else is p53 involved in?

Answer 25

DNA damage repair, blocking angiogenesis | stimulation of apoptosis

Question 26

p53 pathway is _____ in normal cells under normal conditions?

Answer 26

INACTIVE | needs activating by things such as hypoxia, radiation etc

Question 27

p21 inhibiting cyclin/ cdk maintains ____ being hypo-phosphorylated? meaning?

Answer 27

pRb | the complex between pRb and E2F is maintained

Question 28

p53 stimulates its own degredation how?

Answer 28

activating MDM2 | this activates the proteasome and degraded p53

Question 29

what do cells expressing high levels of MDM2 have?

Answer 29

low levels of p53 due to it being degraded

Question 30

how can be target the retinoblastoma tumour suppressor pathway?

Answer 30

inhibiting CDK4 and CDK6

Question 31

what happens when we inhibit CDK4 and 6 in retinoblastoma?

Answer 31

prevent pRb phosphorylation- maintains the E2F complex | this limits expression of genes required for S phase cell cycle progression

Question 32

therapeutic strategies at targeting the p53 pathway? (4)

Answer 32

conversion of mutant p52 to form normal properties prevention of normal p53 interacting with MDM2 gene therapy exploiting synthetic lethality