15th Feb - Intro to Tumour Suppressors and Rb Flashcards
What is a tumour suppressor?
A gene that protects a cell from one or more steps on the path to cancer
What are the three different types of tumour suppressor?
Gatekeepers
Caretakers
Lanscapers
What are gatekeepers?
Tumour suppressors which prevent the growth of potential cancer cells
What are caretakers?
Tumour suppressors which maintain the integrity of the genome
What are Landscapers?
Genes that control the cellular environment
What type of mutation are tumour suppressor mutations i.e. dominant or recessive?
Recessive
What is haploinsufficiency?
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.
What tumour suppressor mutation underlies retinoblastoma?
Rb
What tumour suppressor mutation underlies Li-Fraumeni Syndrome?
p53
What tumour suppressor mutation underlies familial adenomatous polyposis?
APC
What tumour suppressor mutation underlies familial breast cancer?
BRCA
What tumour suppressor mutation underlies neurofibromatosis?
NF1
Who developed the 2-hit hypothesis in 1971?
Alfred Knudson
Outline how Knudson developed his 2-hit hypothesis
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
How can a loss of heterozygosity occur?
Non-disjunction Non-disjunction and duplication Mitotic recombination Gene conversion Deletion Point mutation Promoter methylation
Where is the Rb gene located?
chromosome 13
How was Rb identified to be the cause of retinoblastoma?
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
What are the two proteins related to Rb?
p107 and p130
Outline the normal function of Rb
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
How do Rb levels fluctuate with the cell cycle?
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
Give some examples of E2F target genes and their function
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
