L09 - Tumour Suppressor Genes Flashcards
What is the function of TSGs?
To negatively regulate growth by arresting growth or inducing apoptosis
Why are tumour suppressor genes said to be recessive in cancer?
What is this hypothesis known as?
- Because both alleles of a tumour suppressor gene must be lost to lose tumour suppressor properties
- This is known as Knudson’s two-hit hypothesis:
- Inherited form – one mutation in germ line -> second mutation somatic
- Non-hereditary – both mutations somatic
Why does familial tumour suppressor loss (e.g. with familial retinoblastoma) often result in bilateral disease, whereas somatic tumour suppressor loss often results in unilateral disease (e.g. with somatic retinoblastoma)?
- If the tumour suppressor loss in a particular tissue is familial, the individual is born with one mutated tumour suppressor gene, and the other must be lost by one more somatic mutation in order for tumour suppressor function to be lost
- Since the gene is inherited in both tissues (bilaterally, e.g. in the eyes), familial cancers are more likely to develop bilaterally than unilaterally
- In contrast, an individual that is not born with one mutated tumour suppressor gene must develop two somatic mutations in order for tumour suppressor function to be lost
What are the commonest types of RB1 mutation?
- Large deletions
- Single base substitutions
- Small length mutations
What degree of penetrance is shown by retinoblastoma?
- Most mutations are associated with almost complete penetrance (the autosomal dominant genes)
- Rare alleles show incomplete penetrance
- Although the inheritance of the mutation is dominant, remember that both genes must be lost in order for tumour suppressor function to be lost
How can the second mutation arise in familial and somatic retinoblastomas to cause loss of tumour suppressor function?
1 - There can be a mutation to the second gene, causing hypermethylation of the 5’ region of the nucleotides of the RB1 gene
2 - There can be loss of heterozygosity, which can be a result of mitotic recombination, mitotic nondisjunction or large deletions
*The second point here isn’t specific to retinoblastomas
What does the RB1 gene code for?
How does its protein product work as a tumour suppressor protein?
- The RB1 gene codes for pRB
- pRB must be phosphorylated at the restriction point between G1 and S phase in order for the cell cycle to continue:
- pRB is a transcription factor that represses transcription by repression of E2F transcription factors
- pRB is also bound to HDAC, which antagonises the transcription-priming function of p300
- Early phosphorylation is mediated by the cyclin D - cdk4 / 6 complex. Phosphorylated pRB dissociates from HDAC, enabling transcriptional priming by p300
- Late phosphorylation is mediated by the cyclin E - cdk2 complex. Hyperphosphorylated pRB dissociates from the gene, driving transcription necessary for progression into S phase
What is p16ink4a?
What is its function?
- A tumour suppressor that is expressed in response to cellular stresses that is inactivated in human cancer
- It prevents cdk4 and cdk6 from phosphorylating pRB, causing growth arrest
What are the tumour suppressor functions of p53 transcription factor?
1 - Promotion of proapoptotic activity
2 - Promotion of growth-arresting activity
3 - Promotion of cellular senescence
4 - Inhibition of angiogenesis
How is it possible that over 90% of cancers involve loss of p53 function?
Because although p53 itself is not necessarily lost by mutation in 90% of all cancers, its expression is affected by other upstream mediators
*This reflects the multifactorial process of tumorigenesis
What are Li-Fraumeni and Li-Fraumeni-like syndromes?
- Li-Fraumeni and Li-Fraumeni-like syndromes both have germ-line mutations in the p53 gene
- These are clinically and genetically heterogeneous inherited cancer syndromes that are autosomal dominant, despite being autosomal recessive at the gene level
- The result is early onset of multiple primary tumours, such as sarcomas, breast cancer, brain tumours, leukaemias, and ACC
Describe the structure of p53.
- The transactivation domain regulates transcription
- The proline-rich domain regulates apoptosis
- The sequence-specific DNA binding domain is a transcription factor. Most p53 mutations are
found in this domain, typically in argenine-248, preventing the attachment of p53 to
promoter regions - The oligomerisation domain enables p53 to function as a tetramer
- The regulatory domain integrates signals from other proteins, determining p53 function
When is p53 activated?
- Exists in inactive form in non-stressed cells
- Activated by many forms of stress such as DNA damage (double stranded break at G1-S checkpoint), oncogene activation, hypoxia, loss of adhesion, changes in protein synthesis & ROS
What is mdm2?
- mdm2 inactivates p53
- It is inhibited by p53ARF
- Its expression is also induced by p53 -> mdm2 inactivates excess p53 within cell by poly-ubiquitination
How does p21 inhibit cellular growth?
Inactivates cyclin D-Cdk4/6 & cyclin E-Cdk2 and causes cell cycle arrest
