10: Oncogenes and TS-genes Flashcards
1
Q
What are the hallmarks of cancer?
A
- resisting cell death
- sustaining proliferative signalling
- evading growth suppressors
- activating invasion and metastasis
- enabling replicative immortality
- inducing angiogenesis
AND: - deregulating cellular energetics
- avoiding immune destruction
- tumour-promoting inflammation
- genome instability and mutation
2
Q
Cell cycle - summary of controls
A
- Cycle checkpoints (growth arrest ensures genetic fidelity).
- Specific proteins accumulate/ are destroyed during the cycle -> Cyclins, cycle dependent kinases, cycle dependent kinase inhibitors
- Permanent activation of a cyclin can drive a cell through a checkpoint.
3
Q
Cycle checkpoints
A
- M: check for chromosome attachment to the mitotic spindle
- G1: restriction pointL check for cell size and favourable environmental conditions
- G2: check for damaged or unduplicated DNA; check for unduplicated centrosomes.
4
Q
What are proto-oncogenes? How are they different to oncogenes?
A
- Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation.
- 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)
- Proto-oncogenes can be converted to an oncogene by a SINGLE mutation.
5
Q
Oncogene activation
A
- normal proto-oncogene
- mutation on the coding sequence (point mutation or deletion, etc.) -> aberrantly active protein
- Gene amplification -> multiple gene copies = overproduction of normal protein (e.b. in breast cancer Her2)
- Chromosomal translation (chimeric genes) -> string enhancer increases normal protein levels e.g. Burkitt;s lymphoma
OR
insertional mutagenesis (e.g. viral infection) -> fusion to actively transcribed gene overproduces protein or fusion protein is hyperactive e.g. bcr-abl Philadelphia chromosome. - you can have a promoter put in front of a gene that is not usually expressed.
6
Q
Philadelphia chromosome
A
- 9;22
- BCR-ABL
- ABL: proto-oncogene
- BCR: ?
- seen in CML
7
Q
Slide 12 genes
A
- met; neu (her1,2,3 are part of the neu group) part of phosphorylation tag
- src; ret; [art of phosphorylation tag
- ras; pim-1;
- Myc; fos; jun;
8
Q
Mutant RAS aberrant activity
A
- Upon binding GTP, RAS becomes active.
- Dephosphorylation of the GTP to GDP switches RAS off.
- Mutant RAS fails to dephosphorylate GTP and remains active.
- this leads to increased Raf and activation of downstream pathways such as ERK and therefore proliferation and survival.
9
Q
What are some common oncogenes in human tumours?
A
- SRC
- MYC
- JUN
- Ha-RAS
- Ki-RAS
=> see slide 15 for more info
10
Q
What are tumour suppressor genes?
A
- Typically proteins whose function is to regulate cellular proliferation, maintain cell integrity (e.g. RB -> one of the important parts of the G1-S checkpoint)
- 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 loss of both copies means loss of control.
- keep in mind haploinsufficiency: sometimes one mutation os enough to have the phenotype)
11
Q
Knudson’s two hit hypothesis
A
- For hereditary cancers people already have an inherited mutation and then acquire a mutation later on -> you have to be unlucky once.
- In sporadic cancer, you have to be unlucky twice.
- Haploinsufficiency: in some diseases one mutation is enough to drive the phenotype.
12
Q
Inherited cancer susceptibility
A
- discovery of TS-genes
Features:
- Family history of related cancers (e.g. to get tested for BRCA you have to have a fair history of breast cancer in the family)
- Unusually early age of onset.
- Bilateral tumours in paired organs.
- Synchronous or successive tumours.
- Tumours in different organ systems in same individual.
- Mutation inherited through the germline.
13
Q
Retinoblastoma
A
- Malignant cancer of developing retinal cells.
Sporadic disease 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.
=> lots of families with multiple cases; linked to Cdks.
14
Q
Functional classes of TS-genes
A
- 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 phenotype
+ fit in well with the hallmarks of cancer.
15
Q
What are some common tumour suppressor genes that may be mutated in cancer?
A
- p53 (very difficult to target in cancer therapy because it has so many different roles)
- BRCA1 (important for single strand break repair)
- PTEN
- APC
- p16-INK4A
- MLH1
