Oncogenes and Tumour Surpressors Flashcards
What are the hallmarks of cancer?
- Disregard of signals to stop proliferating
- Disregard of signals to differentiate
- Capacity for sustained proliferation – keep on dividing
- Evasion of apoptosis – continue to divide, despite damaging mutations
- Ability to invade – clinical cancer often only manifests during metastasis
- Ability to promote angiogenesis
What are the stages of the cell cycle?
G0 – the cell is in a quiescent phase – it is not replicating
G1 – the cell makes sure that it has enough nutrients, nucleotides etc. to replicate
S phase - DNA replication
G2 - cell makes sure replication was okay
Mitosis - division to form two daughter cells
What are proto-oncogenes?
- code for proteins involved in maintenance of cell growth, division and differentiation
- mutation converts a proto-oncogene to an oncogene (can be a single-base mutation)
- the protein products of oncogenes no longer respond to control influences
*Oncogenes can be aberrantly expressed, over-expressed or aberrantly active e.g. MYC, RAS, ERB, SIS
How are oncogenes activated?
The normal proto-oncogene may undergo a mutation in its coding sequence - this may produce a gene that codes for an aberrantly active protein
Another way in which activation can occur is gene amplification (multiple gene copies) - there is a LOT more of the protein produced due to amplification, and this is a problem for the cell
( can occur due to problems with a polymerase protein)
- Having multiple copies of a gene will lead to overproduction of the gene produc
Another way of achieving oncogene activation is by chromosomal translocation (chimeric genes)
What are chimeric genes?
genes that are formed by combinations of portions of one or more coding sequences to produce new genes (e.g. the swapping of tips of chromosomes)
There is a swap over of genetic material during division
- This can be a problem if one of the pieces of translocated DNA is a promoter, leading to upregulation of the other gene portion (this occurs in Burkitt’s Lymphoma)
- INSERTIONAL MUTAGENESIS: This can also be a problem if the fusion gene formed produces an abnormal protein (e.g. Philadelphia chromosomes in CML)
What is the Philadelphia chromosome?
translocation of chromosome segments from chromosome 9 (ABL) and 22 (BCR) -> ABL-BCR fusion gene -> cancer
How do different mutations in proto-oncogenes lead to cancers?
(gene, function, mechanism of activation, location, associated human cancer)
SRC
function: tyrosin kinase
mechanism of activation: overexpression/ c-terminal deletion
location: cytoplasmic
associated human cancer: breast, colon, lung
MYC function: transcription factor mechanism of activation: translocation location: nuclear associated human cancer: Burkitt's lymphoma
JUN function: transcription factor mechanism of activation: overexpression/deletion location: nuclear associated human cancer: lung
Ha-RAS function: g proten mechanism of activation: point mutation location: cytoplasmic associated human cancer: bladder
Ki-RAS function: g proten mechanism of activation: point mutation location: cytoplasmic associated human cancer: colon, lung
What does RAS code for?
family of proteins (e.g Ki-RAS and Ha-RAS) which are membrane bound GTPases that are important in stimulation of cell proliferation
What does mutant RAS do?
Normally, upon binding GTP, RAS becomes active -> when bound to GTP, it is active so it interacts with a protein called RAF and signals via phosphorylation -> activates the kinase cascade leading to the production of gene regulatory proteins -> RAS passes the signal on to other proteins within a signal transduction cascade
- The cell goes into a PROLIFERATIVE PHASE
- Dephoshorylation of the GTP to GDP to switch RAS off
Mutant RAS will fail to dephosphorylate GTP, meaning that the GTP persists so RAS remains active -> INCREASED SIGNALLING with the RAF protein -> continuous proliferative stimulation
- The Ras pathway is part of a much more complex signalling cascade called the mitogen-activated protein kinase cascade (MAPK)
What are tumour suppressor genes?
regulate cellular proliferation, maintain cell integrity e.g. RB
- Each cell has two copies of each tumour suppressor gene – BOTH must be damaged to promote cancer - mutation/deletion of one gene copy is usually insufficient to promote cancer (two-hit hypothesis) UNLESS the mutant gene acts dominant (e.g. p53 – exception)
What are the features of inherited cancer genes?
Give an example
- family history of related cancers
- Unusually early onset – the mutation often only affects ONE COPY
- Bilateral tumours in paired organs
- Synchronous or successive tumours
- Tumours in different organ systems in same individual
- Mutation inherited through the germline
retinoblastoma -malignant cancer of developing retinal cells
- Sporadic disease usually involves one eye
- Hereditary causes can be unilateral or bilateral and multifocal
- It is caused by mutation of the RB1 tumour suppressor gene on the chromosome 13q14 (RB1 encodes a nuclear protein that is involved in regulation of the cell cycle)
What are the functional classes of TSGs?
- 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
- all lead to suppression of neoplastic phenotype
What are some TSGs?
gene, function, location and associated human cancer
p53
function: cell cycle regulator
location: nuclear
associated human cancer: many (colon, breast, bladder, lung etc.)
BRCA1
function: cell cycle regulator
location: nuclear
associated human cancer: breast, ovarian, prostate
PTEN
function: tyrosin and lipid phosphatase
location: cytoplasmic
associated human cancer: prostate, glioblastoma
APC
function: cell signalling
location: nuclear
associated human cancer: colon
p16 (-INK4A)
function: cell cyle regulator
location: nuclear
associated human cancer: colon and others
MLH1
function: mismatch repair
location: nuclear
associated human cancer: colon, gastric
What is p53? What is it’s function?
cell cycle regulator with a nuclear location. It is expressed in its mutated form in 50% of all human tumours
When a cell has DNA damage, p53 increases to induce G1 arrest, in attempt to resolve the problem
If it repairs the cell, life continues as normal. If the damage is too bad, p53 will commit the cell to apoptosis
In a cell where p53 is dysfunctional, there will be no repair response.
We end up with cells that carry mutations (precursors of cancer). If damage is overwhelming, the cell is likely to go into mitotic failure.
What moderates p53?
Mdm2 protein - stops p53 being active
cellular distress/ DNA damage activates p53
