Cancer 2 - Oncogenes and Tumour Suppressors Flashcards
In the cell cycle, what is the G0 phase
The quiescent phase - cell not replicating
What occurs during the G1 phase?
Cell ensuring it has enough nutrients, nucleotides, etc for replication
What happens at the end of G1, and why?
Growth arrest (checkpoint) - ensures genetic fidelity of the cell
Name 3 proteins that accumulate and are destroyed during the cell cycle
- Cyclins
- Cyclin-dependant kinases
- Cyclin-dependant kinase inhibitors
What does permanent cyclin activation do?
Ceases growth arrest and causes cell to drive through checkpoints
What can a mutation to a proto-oncogene do?
Cause it to become an oncogene, whereby the protein product does not respond to control influences
Proto-oncogene can become an oncogene through a single mutation
4 ways in which oncogene activation can occur
- Mutation in coding sequence
- Gene amplification
- Chromosomal translocation
- Insertional mutagenesis
What may cause gene amplification to occur?
What can having multiple copies of a gene cause?
Problems with polymerase protein may cause gene amplification
Multiple copies of a gene = overproduction of gene product
What are chimeric genes?
Genes formed by combining parts of 1/more coding sequences - resulting in new genes (e.g. swapping tips of chromosomes)
What happens in Burkitts lymphoma
One of the translocated pieces of DNA is a promotor which leads to up regulation of the other gene portion (i.e. promotor acts as a strong enhancer)
Give an example of when a fused gene can form an abnormal protein?
Philadelphia chromosome in CML
Which 2 chromosome segments are translocated to form the Philadelphia chromosome?
Chr 9 - ABL
Chr 22 - BCR
Results in BCR-ABL fusion gene on Chr 22 - development of cancer
Why are proto-oncogenes critical gene targets?
They regulate signal transduction pathways
What is Ras and what does it normally do?
It is part of a pathway involved in producing gene regulatory pathways - Ras part of a family of membrane bound GTP-ases important in cell proliferation.
It binds to GTP and activates the kinase cascade - it is switched off when GTP is dephosphorylated to GDP
What cascade is Ras part of?
Mitogen activated protein kinase cascade (MAPK)
What happens in mutant Ras?
Mutant Ras fails to dephosphorylate GTP - so no GDP so Ras remains active
What are the main functions of tumour suppressor genes?
Regulate cellular proliferation and maintain cell integrity
How many copies of a TSG does a cell have?
2 - mutation/deletion of 1 TSG is usually insufficient to cause cancer
What are the features of inherited cancer susceptibility (non functioning TSGs)
- Family history of related cancers
- Early onset
- Bilateral tumours in paired organs
Give an example of an inherited cancer?
Retinoblastoma
What mutation causes retinoblastoma
RB1 TSG on chromosome 13q14
What does RB1 encode?
Nuclear protein involved in regulating cell cycle
What is the overall function of TSGs?
To suppress the neoplastic phenotype
When p53 is bound to _____ it is inactive
MDM2
What is p53
It is a TSG but it requires only a mutation of a single copy to get dysregulation - p53 mutants act in a dominant manner
What does p53 do?
It is triggered by cellular stressors (physiological and severe)
It is involved in regulating p53 target genes and protein-protein interactions
How is p53 stabilised so it isn’t degraded quickly and can exert its effects
It is phosphorylated
What can mutation of the APC tumour suppressor gene cause?
Familial Adenomatous Polyposis Coli (FAPC)
What causes FAPC
Deletion in 5q21 - results in loss of APC tumour suppressor gene
Are the polyps cancerous in FAPC
NO
But there is a 90% risk of developing colon cancer
How does APC protein prevent uncontrolled growth?
Helps control Beta-catenin activity and also is involved in the WNT signalling pathway
What 2 factors may cause polyps to develop into adenomas?
DNA hypomethylation & K-ras mutation
Both TSG and oncogenes are involved in development of colorectal cancer
APC gene (TSG) K-ras (oncogene)
Are TSG or oncogenes caused by deletion/mutations?
TSG inactivated by deletions/mutations
Oncogenes caused by specific translocations / point mutations
