Oncogenes and Tumour Suppressors Flashcards
What are the six hallmarks of cancer?
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
What are the two emerging hallmarks of cancer?
What are two enabling characteristics?
Deregulating cellular energetics
Avoiding immune destruction
Genome instability and mutation
Tumour-promoting inflammation
Differentiate between proto-oncogenes and oncogenes.
In what ways may the oncogene function differently?
Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation.
Mutation (can be a single mutation) converts a proto-oncogene to an oncogene, whose protein product no longer responds to controller influences.
Oncogenes can be aberrantly expressed, over-expressed or aberrantly active.
What are the different types of oncogene activation/mutant proto-oncogenes?
- Mutation in the coding sequence (point mutation or deletion)
- Gene amplification (production of multiple gene copies)
- Chromosomal translocation (Chimaeric genes)
- Insertional mutagenesis (e.g. viral infection)
When can the formation of chimeric genes be a problem? Give and example of a cancer.
- If one of the pieces of translocated DNA is a promoter, it could lead to upregulation of the other gene portion (this occurs in Burkitt’s lymphoma)
- If the fusion gene codes for an abnormal protein that promotes cancer (e.g. Philadelphia chromosome)
What is the Philadelphia Chromosome?
Chromosome produced by the translocation of the ABL gene (strong promoter) on chromosome 9 to the BCR gene on chromosome 22
The BCR-ABL fusion gene encodes a tyrosine kinase receptor that does not switch off and thus drives uncontrolled proliferation
Give examples of different signal transduction proteins that are proto-ongogenes.
Tyrosine kinase receptors – met, neu, src, ret
Transcription factors – myc, fos, jun.
GPCR g-proteins – ras, gip-2.
Kinases – raf, pim-1.
State the mechanism of activation to an oncogene for src, myc, jun, Ha-ras, and Ki-ras.
State an associated human cancer for each.
SRC = Overexpression/ C-terminal deletion MYC = Translocation JUN = Overexpression/ deletion Ha-RAS = Point mutation Ki-RAS = Point mutation
SRC = Breast, colon, lung MYC = Burkitt’s lymphoma JUN = Lung Ha-RAS = Bladder Ki-RAS = Colon, lung
List the functional classes of Tumour Suppressor Genes
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
Why is a mutation/deletion of ONE TSG copy (usually) insufficient to promote cancer?
Each cell has two copies of each tumour suppressor gene.
Only a mutation or loss of both copies means loss of control.
= Knudson’s two hit hypothesis (either 2 acquired mutations or 1 inherited + 1 acquired mutation)
List some typical features of cancers involving TSGs
- Family history of related cancers.
- 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.
Give an example of a tumour suppressor gene and describe the mutation that leads to cancer
Example – Retinoblastoma:
- Mutation of RB1 TSG on Chr 13q14 => Malignant cells of developing retinal ganglionic cells.
- RB1 encodes a nuclear regulation protein.
- A sporadic disease usually involving one eye. The hereditary versions can be uni/bilateral or multifocal (multiple tumours).
State some important tumour suppressor genes in human cancers. State the associated cancers corresponding to each TSG.
p53 – cell cycle regulator
BRCA1 – cell cycle regulator
PTEN – tyrosine and lipid phosphatase
APC – cell signalling
Many (colon, breast, bladder, lung etc)
Breast, ovarian, prostate
Prostate, glioblastoma
Colon
In what form is p53 inactive?
When it is bound to MDM2
What is p53 important for?
It is important for regulation of p53 target genes (involved in DNA repair, growth arrest, senescence etc.) and protein-protein interactions (e.g. apoptosis)
