15th Feb - Intro to Tumour Suppressors and Rb

Question 1

What is a tumour suppressor?

Answer 1

A gene that protects a cell from one or more steps on the path to cancer

Question 2

What are the three different types of tumour suppressor?

Answer 2

Gatekeepers
Caretakers
Lanscapers

Question 3

What are gatekeepers?

Answer 3

Tumour suppressors which prevent the growth of potential cancer cells

Question 4

What are caretakers?

Answer 4

Tumour suppressors which maintain the integrity of the genome

Question 5

What are Landscapers?

Answer 5

Genes that control the cellular environment

Question 6

What type of mutation are tumour suppressor mutations i.e. dominant or recessive?

Answer 6

Recessive

Question 7

What is haploinsufficiency?

Answer 7

Haploinsufficiency is often caused by a loss-of-function mutation, in which having only one copy of the wild-type allele is not sufficient to produce the wild-type phenotype.

Question 8

What tumour suppressor mutation underlies retinoblastoma?

Answer 8

Rb

Question 9

What tumour suppressor mutation underlies Li-Fraumeni Syndrome?

Answer 9

p53

Question 10

What tumour suppressor mutation underlies familial adenomatous polyposis?

Answer 10

APC

Question 11

What tumour suppressor mutation underlies familial breast cancer?

Answer 11

BRCA

Question 12

What tumour suppressor mutation underlies neurofibromatosis?

Answer 12

NF1

Question 13

Who developed the 2-hit hypothesis in 1971?

Answer 13

Alfred Knudson

Question 14

Outline how Knudson developed his 2-hit hypothesis

Answer 14

He noticed that patients with familial retinoblastoma presented earlier on in life than sporadic retinoblastoma.

Thus he concluded that something predisposes these patients to cancer, therefore there must be an anti oncogene

Question 15

How can a loss of heterozygosity occur?

Answer 15

Non-disjunction
Non-disjunction and duplication
Mitotic recombination
Gene conversion
Deletion
Point mutation
Promoter methylation

Question 16

Where is the Rb gene located?

Answer 16

chromosome 13

Question 17

How was Rb identified to be the cause of retinoblastoma?

Answer 17

Patients with familial retinoblastoma all had visible alterations of chromosome 13. Sporadic patients had deletions in the same region of chromosome 13. Using the known chromosomal location the gene was cloned and sequenced in 1986

Question 18

What are the two proteins related to Rb?

Answer 18

p107 and p130

Question 19

Outline the normal function of Rb

Answer 19

It suppresses G1-S transition by binding to E2F 1/2/3 and DP 1/2 in its monophosphorylated form, recruiting HDACs.

When it is further phosphorylated it dissociates, allowing E2F 1/2/3 and DP 1/2 to function –> HAT recruitment and G1–>S transition

POSITIVE FEEDBACK LOOP: As Cdk2 is produced it further phosphorylates Rb making the transition irreversible

Question 20

How do Rb levels fluctuate with the cell cycle?

Answer 20

Early/mid G1 - pRb present inhibiting E2F 1/2/3
Late G1 - pRB is hyperphosphorylated, E2F 1/2/3 is active
S phase - No E2F 1/2/3 is present, Rb is hyperphosphorylated

Question 21

Give some examples of E2F target genes and their function

Answer 21

MCM5 - DNA synthesis and replication
Beta-lactamase - Metabolism
BRCA1 - DNA repair
CDC25 - Mitosis
TGF beta - Apoptosis
Myc - TF
HP1 alpha - Chromatin assembly
cdk2 - Cell cycle