19.06.01 Tumour suppressor genes Flashcards
What are tumour suppressor genes
-Encode proteins that prevent inappropriate cell growth and division and stimulate cell death. Their loss/inactivation gives rise to malignancy
What are the three tumour suppressor genes subgroups
- Gate keepers: encode proteins that control the cell cycle and regulate cell proliferation (p53, APC, Rb)
- Caretaker genes: maintain and protect the integrity of the genome. Involved in DNA repair and prevent accumulation of mutations (MLH1, MHS2)
- Landscaper: help create environments that control cell growth. Loss of these cause the microenvironment to become abnormal and promote transformation of normal epithelial cells (e.g. PTEN)
Mechanisms to control cell growth and division
- Restrain cell growth. Either by controlling progression within the cell cycle. Or inhibit proliferation.
- Maintain integrity of genome
- Stimulate cell death
Retinoblastoma
- Aggressive childhood cancer of the eye.
- Can be unilateral or bilateral
- Incidence= 1 in 15,000/20,000 live births.
- 10-20% are large structural variants
- 80-90 single base substitutions or indels
- LOF associated with complete penetrance and severe phenotype compared to missense.
- 60-70% tumour exhibit loss of heterozygosity with a mutation in the other allele.
- third of retinoblastomas are hereditary
- Rb gene, 13q14
- Encodes pRB as nuclear phosphoprotein
- Protein pock family. Pocket is a conserved protein interaction domain that acts as a transcriptional repressor.
- Role in cell cycle progression, chromosome stability and regulation of apoptosis
- phosphorylated by CDKs, becoming inactive. E2Fs are then release to activate transcription, leading to cyclin E production and entry into S phase.
What is knudson’s two hit hypothesis
- Discovered by studying retinoblastoma and differences between sporadic and hereditary RB
- Both forms require two hits to RB gene.
- Hereditary form: a mutant allele is inherited. Later a somatic mutation inactivates the normal allele leading to disease development. Variable penetrance.
- Sporadic form: 2 somatic events occur. Second hit must occur in descendants of cell with first hit. Second mutation could be LOH, promoter methylation (gene silencing), mutation or deletion.
What does p53 do
- Central component of signalling pathways essential for cell growth, regulation and apoptosis.
- Induced by non-genotoxic stresses (oxidative stress, hypoxia, double strand breaks)
What regulates p53 levels
MDM2 (E3 ubiquitin ligase). When phosphorylated it migrates to nucleus and binds to p53, causing it to be degraded by ubiquitin pathway.
Causes of loss of p53
- Mutations in gene upstream of p53, p53 cannot be activated. e.g. ATM, CHK2.
- Mutations in p53 (50% of tumours have somatic variants in p53). Li-Fraumeni syndrome cause by p53 germline mutations.
- Mutations downstream of p53. e.g. PTEN. Cowden syndrome.
What does CDKN2A regulate
RB and p53
What does CDKN2A encode
p16INK4A (inhibits RB) and p14ARF (inhibits p53)
Can microRNAs function as TSGs?
Yes. Can be used as markers of disease, prognosis, therapeutic targets. Interact with p53
Example of a tumour suppressor miRNAs
- miR-34 family.
- Lost in lung cancer.
- miR-34a promotes p53-mediated apoptosis
- Required for radiation response