Cancer #4

Question 1

Role of tumour suppressor genes (TSG)

Answer 1

inhibition of cell division via:
~ negative regulation
~ activating cell death
decreases in TSG lead to cancer

Question 2

Retinoblastoma

Answer 2

most common eye tumour in children
~ routinely checked for - white light shone in eye
red = normal
white = chance of tumour
~ can be sporadic or hereditary
~ RB tumour suppressor gene affected

Question 3

Knudson’e two hit mutation hypothesis

Answer 3

retinoblastoma is caused by two mutational events
hereditary = one inherited via germline cells and the 2nd occurs in somatic cells (loss of heterozygosity)
sporadic = both mutations in somatic cells

Question 4

The cause of loss of heterozygosity is…

Answer 4

homologous recombination in prophase of meiosis I

Question 5

Role of RB

Answer 5

regulates the passage of cells form G1 to S phase by sequestering E2F
E2F activates genes required for G1/S transition
MUTATED rb/rb cells –> pRB is truncated, unstable so fails to bind to E2F –> cells transition into S phase

Question 6

p53

Answer 6

transcription factor

a.k.a. guardian of the genome

Question 7

Li-Fraumeni syndrome

Answer 7

associated with inheritance of a mutated p53 allele

90% risk of developing cancers

Question 8

p53 functions as a…

Answer 8

tetramer

Question 9

p53 + no DNA damage

Answer 9

MDM2 ubiquitinates lysine in p53 C-terminal domain = targets it for degradation
~ any remaining p53 is exported from the nucleus

Question 10

p53 + DNA damage

Answer 10

DNA damage = activates kinases = phosphorylation go MDM2 and p53 (they cannot interact) = p53 tetramerizes and block nuclear export
~ p53 accumulates and interacts with transcription proteins (e.g. p300) –> acetylates histones and p53 = enhanced transcription
~ accumulation of p53 is meant to arrest the cell cycle

Question 11

Which genes does p53 active the transcription of?

Answer 11

p21
GaDD45
14-3-3sigma
Bax
APAF1
FAS cell surface death receptors

Question 12

p21

Answer 12

inhibits cyclin-dependent kinases

arrests cells at G1/S boundary

Question 13

GaDD45

Answer 13

binds and blocks PCNA

S-phase DNA rep. check point

Question 14

14-3-3sigma

Answer 14

binds and sequesters CDC25 –> required for activation of cyclinB-cdk1 activation
G2/M boundary

Question 15

Bax

Answer 15

positive regulator of apoptosis

Question 16

APAF1

Answer 16

activates camasses = intrinsically apoptosis pathway

Question 17

FAS cell surface death receptors

Answer 17

extrinsic apoptosis pathway

Question 18

Loss of wt p53 in tumour cells can lead to…

Answer 18

1) no activation of DNA damage checkpoint
2) no cell cycle arrest
3) apoptosis inhibited

Question 19

Increased genetic instability leads to…

Answer 19

increased chance of further mutations that may activate oncogenes, or result in loss of tumour suppressor genes

Question 20

Types of p53 inactivating mutations

Answer 20

1) UV causing C–>T or CC–>TT
2) mutations in DNA bases due to polycyclic hydrocarbons
~ one bad monomer can poison tetramer
~ p53 can also be inactive by its sequestration

Question 21

Gatekeeper TSGs

Answer 21

directly involved in restraining cell proliferation

e.g. p53, p21, RB and Bax

Question 22

Caretaker TSGs

Answer 22

maintain the integrity of the genome

e.g. BRCA1, BRCA2

Question 23

BRCA1 and BRCA2

Answer 23

~ large nuclear proteins
~ promote repair of DNA DSBs by high-fidelity homologous recombination
~ mediated by Rad51