Lecture 20 Flashcards
What are tumour suppressor genes?
Genes which decrease the rate/inhibit cell division
How do TSG inhibit cell division?
- Inhibit cell division
- Promote cell death
- Negative regulation of proliferative signalling
What type of mutations cause cancer and inhibit TSG
Point mutations
Chromosomal mutations
Genetically recessive
What are retinoblastomas?
Most common eye tumour in children aged 0 to 4
How are children screened for retinoblastomas?
- White light is shone in eye
Red light reflect - Normal
White light reflect - Retinoblastoma
What percentage of children die from retinoblastomas
87%
2 types of retinoblastomas
Sporadic (60%) - No family history, unilateral, single tumour in 1 eye
Hereditary - Bilateral, multiple tumours in both eyes
Knudson’s 2 hit mutation hypothesis
- Retinoblastoma caused by 2 mutational events
One inherited by germinal cells
One occurs in somatic cells
Sporadic cases both occur in somatic cells
Genetics of retinoblastoma
RB tumour suppressor gene
180kb gene
4.7kb mRNA
Familial retinoblastoma - Loss of wild type RB allele - Loss of heterozygosity
What can lead to loss of heterozygosity?
Mitotic recombination
pRB in G1 to S regulation
- Progession through restiction point is pivotal in tumourigenesis
- rb/rb cells - pRB often truncated and fails to bind to E2F
- E2F free to activate genes for G1/S transition and S-phase
- Loss of pRB causes sustained proliferative signalling
p53 Tumour supressor gene
- Most commonly mutated gene in humans cancer - almost 50% of all sporadic mutations
- p53 protein - transcription factor named guardian of genome
- Li-Fraumeni syndrome associated with mutated p53 allele inheritance - 90% risk of cancer
- Tumours develop when p53 gene lost
How does p53 accumulate in response to DNA damage?
- MDM2-p53 disrupted by phosphorylation
- Tetramerization of p53 blocks nuclear export, increasing nuclear concentration
- Phosphorylated p53 interacts with histone acetylase p300
- Acetylates histone and p53
Major roles for p53
RB1 and accessory tumour suppressor proteins as brakes on cell divsion
What genes does p53 activate?
- p21 - Inhibits CDKs which arrest cells at G1/S
- GADD45 - Binds to PCNA - Prevents PCNA becoming a processivity factor
- 14-3-3o - Binds and sequesters cdc25 phosphatase - Prevents removal of inhibitory phosphorylation on Y15 of Cdk1 - arrests cells at G2/M boundary
- Bax - Pro-apoptotic
- FAS cell surface death receptors - extrinsic apopotosis
- APAF1 - Activates caspases - Intrinsic apoptosis
Downstream events trigged by p53
Loss of p53 causes:
- No activation of DNA damage checkpoint
- No cell cycle arrest
- Apoptosis inhibited
What does increased genetic instability cause?
Increased risk of activated oncogenes or inhibition of TSGs
Loss of p53 activity by inactivating mutation
Initiating mutation - may be caused by environment
Can cause skins and lung cancers e.g. basal cell carcinoma
Most p53 mutations recessive
Some have dominant negative effect - Can affect tetramer function
Loss of p53 activity by degradation
~3000 women diagnosed annually with cervical cancer in UK
- Human papillomaviruses main cause of cervical cancer with type 16 and 18 - 70%
- HPV produces E6 and E7 oncoproteins
- E6 binds to p53 for targeted destruction
- E7 oncoprotein sequester Rb - degrades E2F activity
Gatekeeper TSGs
- p53 mutation - Loss of G1/S, S and G2/M checkpoints
- p21 mutation - Loss of G1/S and S checkpoints
- RB mutation - Promotes proliferation, E2F uninhibited
- Bax mutation - No apoptosis
Caretaker TSGs
Genes coding for protein mediating DNA repair
Loss of function leads to genome instability
Increases chances of loss of further TSGs and mutation of proto-oncogenes to oncogenes
Mutations cause familial cancer
Lynch syndrome
- Autosomal dominant
- 80% chance of colon cancer
- Mutant allele of one of the mismatch genes MSH2, MLH1, PMS1, and PMS2
- Patients developing hereditary non-polyposis colon cancer (HNPCC) are heterozygous, tumours show LOH
Xeroderma pigmentosum
- Autosomal recessive
- Skin cancer susceptibility
- Defective NER
- Failure to repair UV inflicted DNA damage
Mutations in caretaker genes BRCA1 and BRCA2 linked to increased risk for breast and ovarian cancer
- 10% breast cancer associated with inherited mutation in BRCA1 or 2
- BCRA1 and BCRA2 large unrelated nuclear proteins
-In normal cells BRCA1 and BRCA2 promote repair of DNA DSBs by high-fidelity homologous recombination - mediated by RAD51, human homologue of RecA - Tumours show LOH
