L08-* Tumour suppressor genes Flashcards
What is a tumour suppressor gene?
They are genes that transcribe proteins that negatively regulate cell growth and are checkpoints of the cell cycle.
What is Knudson’s two hit hypothesis and what is the result of this?
As tumour suppressor genes tend to be recessive then both alleles must be abolished for the tumour suppressor properties to be abolished. This means that two mutations are required ‘two hits’. These can either be both somatic mutations or more likely to occur is one is inherited as a germ line mutation and then one is a somatic mutation.
What is retinoblastoma?
It is a cancer of the retina that typically occurs in young children. It results in thickening of the optic nerve and displacement of the normal retina cells. It results from mutations in both of the alleles of the pRB tumour suppressor gene.
How does bilateral retinoblastoma occur?
This is 100 percent familial as requires a germ line mutation being present for it to be likely enough to occur in both eyes. Therefore will only require one somatic mutation to reach homologous state.
What is the penetrance of familial retinoblastoma?
Most mutations show almost complete penetrace and an autosomal dominant inheritance pattern. This is because whilst there is still a recessive pattern at the cellular level there is already a germ line mutation so only one somatic mutation is required to cause homozygous state.
What are the differences in presentation of somatic and familial retinoblastoma?
Familial retinoblastoma: Only need 1 mutation to get to homozygous state, so presents earlier as well as bilaterally.
Somatic retinoblastoma : Need 2 mutations to get to homozygous stateand thus presents later and unilaterally.
What is the role of pRB in cell cycle control?
pRB acts as a checkpoint in the cell cycle that prevents passage from the G1 to the S phase. This acts to prevent the cell replicating damaged DNA. It does this by binding to transcription factors in the E2F family and preventing them from working.
How does transcription normally occur at the G1 checkpoint?
Cyclin levels activate cyclin dependent kinases. These phosphorylate pRB which acts as transcription repressor when it is hypophosphorylated. After being phosphorylated it becomes hyperphophorylated and releases the E2F transcription factors it is bound to. Free E2F can then transcribe genes and allow entry into the S phase.
What is p16ink4a and what does it do?
This is another tumour suppressor gene, increased cellular stress increases transcription of its protein. The protein inhibits phosphorylation of pRB hence causing cell cycle arrest.
How often is the p53 pathway inactivated?
It is inactivated in 90+% of cancers, may not be mutation in p53 but in some way its function is inhibited.
How does p53 normally function?
It is normally in a negative feedback loop with MDM2. p53 is usually in low concentrations in the cell and an increase in p53 causes an increase in MDM2 levels. MDM2 is a ubiquitin protein ligase and causes p53 degradation.
How is p53 activated?
Cellular stresses such as hypoxia or reactive oxygen species cause phosphorylation of p53. This is through mediators such as ATM and 19ARF. As well as phosphorylating p53 these mediators inhibit MDM2 so p53 can become active and perform its function.
What is the action of p53?
It transcribes several genes which inhibit angiogenesis, induces growth arrest, DNA repair and pro apoptotic activity.
What is the role of p53 in the G1 S checkpoint?
When activated p 53 transcribes p21 which inhibits the cyclins in the G1-S checkpoint. This means that they are unable to phosphorylate pRB so the cell cycle is arrested.
How does p53 induce apoptosis?
Through both transcriptional and non-transcriptional mechanisms cyctochrome C is released from mitochondria. This causes formation of of the apoptosome.
