Cancer 2: Oncogenes and tumour suppressors Flashcards
Describe the cancer cell phenotype?
- Disregard of signals to stop proliferating.
- Disregard of signals to differentiate.
- Capacity for sustained proliferation.
- Evasion of apoptosis.
- Ability to invade.
- Ability to promote angiogenesis.
Describe the relevance of the cell cycle slide
G0 - quiescent phase
G1, S (duplication of chromosomes), G2 (checking phase), M (mitotic phase)
This cycle is tightly controlled. There are cycle checkpoints which cause growth arrest to ensure genetic fidelity.
Key protein such as cyclins can be over produced and drive cells through these checkpoints = cancer
Define proto-oncogenes
Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation.
What happens during a mutation of a proto-oncogene?
Mutation (can be a single mutation) converts a proto-oncogene to an oncogene, whose protein product no longer responds to control influences.
Oncogenes can be aberrantly expressed, over-expressed or aberrantly active. e.g MYC, RAS, ERB, SIS
What are the different ways oncogenes can be activated?
- mutation in the coding sequence (point mutation deletion) –> Aberrantly active protein
- gene amplification (multiple gene copies) –> overproduction of normal protein
- Chromsomal translocation (chimaeric genes) –> Strong enhancer increases normal protein levels e.g Burkitt’s lymphoma
Fusion to actively transcribed gene overproduces protein or fusion protein is hyperactive. e.g Philadelphia chromosome (fusion of ABL gene of chromosome 9 and BCR gene of 22 - powerfully expressedp) - Insertional mutagenesis (e.g viral infection) –> Can cause the same kind of problems as chromosomal translocation
What are potential critical gene targets causing cancer?
Proteins involved in signal transduction
Nuclear or cytosolic receptor –> affects DNA –> transcription/translation –> proliferation
Tyrosine kinase receptor –> phosphorylation –> proliferation
G-protein coupled receptor –> kinase enzyme –> phosphorylation –> proliferation
Protooncogenes produce proteins that are key to signalling - if they are damaged you get inappropriate signalling.
See slide
Describe the Ras protein and cancer
Ras is activated on binding with GTP, it subsequently activates other proteins (RAF which is released from RAS when activated), which cause cell growth, differentiation and survival. PROLIFERATION. Ras is tethered to the membrane
Dephosphorylation of the GTP to GDP switches RAS off. Normal RAS dephosphorylates GTP.
Mutant RAS fails to dephosphorylate GTP and remains active = meaning constant PROLIFERATION
Describe the RAS signalling pathway?
See slides
Oncogenes and human tumours?
Damage to a single copy of a proto-oncogene will leave to an oncogene which will drive the cancer process.
SRC damage –> breast, colon and lung tumours
Ha-RAS (g protein) –> bladder tumours
Ki-RAS –> colon and lung tumour
Different tumours have different oncogenes associated with them.
What are tumour suppressor genes?
These genes typically produce proteins whose function is to regulate cellular proliferation, maintain cell integrity E.g RB (gene involved in retinoblastoma)
Opposite function of proto-oncogenes
Each cell has two copies of each tumour suppressor gene.
Mutation or deletion of one gene copy is usually insufficient to promote cancer.
Mutation or lost of both copies means loss of control.
What are the features of inherited cancer susceptibility?
Normally cancer is a disease of age.
This is how tumour suppressor genes were discovered.
Features:
- Family history of related cancers.
- Unusually early age of onset (suggests inherited)
- Bilateral tumours in paired organs (e.g tumours of both kidneys)
- Synchronous or successive tumours.
- Tumours in different organ systems in same individual.
- Mutation inherited through the germline.
Describe retinoblastoma
- Malignant cancer of developing retinal cells.
- Sporadic disease (age) usually involves one eye.
- Hereditary cases can be unilateral or bilateral and multifocal.
- Due to mutation of the RB1 tumour suppressor gene on chromosome 13q14.
- RB1 encodes a nuclear protein that is involved in the regulation of the cell cycle.
What are the functional classes of tumour suppressor genes? What do they do?
Regulate cell proliferation
Maintain cellular integrity
Regulate cell growth
Regulate the cell cycle
Nuclear transcription factors
DNA repair proteins
Cell adhesion molecules
Cell death regulators
- Suppress the neoplastic phenotypeDescribe the p53 gene
Acts as the guardian of the genome - has many mechanisms of anticancer function.
Although p53 is a tumour supressor gene, mutants of p53 act in a dominant manner and mutation of a single copy is sufficient to get dysregulation of activity.
p53 requires a single gene mutations to damage one copy of it to cause it to act like a oncogene (even though it is a tumour suppressor gene - remember you need both tumour suppressor genes to be defective for cancer to develop)
p53 bound to MDM2 when it is not needed –> when needed to it is released. Reasons to release it is multifactorial. p53 dimerises with other p53 molecules to act as a functional unit.
See slides
What is the APC tumour suppressor gene? What happens if deletion occurs?
This is a tumour suppressor gene - involved in cell adhesion and signalling.
Familial adenomatous polyposis coli - deletion in 5q21 = loss of APC. It is in a hyperproliferative state.
Sufferers develop multiple benign adenomatous polyps of the colon. This is not cancer.
There is a 90% risk of developing colorectal carcinoma.
