Oncogenes and Tumour Suppressor Genes Flashcards
what are the 6 hallmarks of cancer?
o Disregard signals to stop proliferating. o Disregard signals to differentiate. o Capacity for sustained proliferation. o Evasion of apoptosis. o Ability to invade. o Ability to promote angiogenesis. \+ avoid immune destruction \+ tumour promoting inflammation \+ genome instability and mutation
what ensure genetic fidelity?
Cycle checkpoints
what do proto-oncogenes code for?
essential proteins involved in maintenance of cell growth, division and differentiation.
produce normal protein, expressed normally and respond to signals appropriately
what does a mutated proto-oncogene produce?
oncogene (whose protein product does NOT respond to control influences)
how can oncogenes be active?
be aberrantly expressed, over-expressed or aberrantly active
what is the minimal requirement for a proto-oncogene to become an Oncogene?
can be converted to an oncogene by A SINGLE MUTATION.
what are the 4 ways a normal proto-oncogene can become an oncogene?
- Mutation in the coding sequence
- leading to an aberrant protein - Gene amplification
- leading to overproduction of the normal protein - Chromosomal translocation e.g chimeric genes
- enhancer added to increase normal protein levels - Insertional mutagenesis e. g viral infection
- fusion protein created is hyperactive
what are the mutations that can occur in a coding sequence?
Point mutation or deletion.
what happens in gene amplification?
A protein may block the DNA polymerase so the polymerase repeatedly backs up to go over the area a few times creating many identical genes.
what genes are produced in chromosomal translocation?
Chimeric genes.
example of gene created by chromosomal translocation?
Philadelphia chromosome (translocation between Chr 9 and 22)
Bcr-abl encodes a tyrosine kinase receptor that does not switch off which is anti-apoptotic enable cancer cell survival
leads to CML
what is insertional mutagenises?
Viral infections – some viruses insert their genome into our DNA and usually this isn’t a problem as much of our DNA does not code but if it’s in a coding region, this could be cancer.
examples of proto-oncogenes and proteins they produce?
o Tyrosine kinase receptors EC – met, neu.
o Tyrosine kinase receptors IC – src, ret.
o Transcription factors – myc, fos, jun.
o GPCR g-proteins – ras, gip-2.
o Kinases – raf, pim-1.
how is Ras switched on and switched off?
binding GTP, RAS becomes active and it’s dephosphorylation of GTP to GDP switches RAS off.
what does Ras binding to GTP enable?
allows RAS to bind RAF and pass the signal to RAF deliver the signal further to MEK and ERK.
Dephosphorylation unbinds Raf from Ras
what does mutant Ras do?
fails to dephosphorylate GTP and remains active and bound to RAF and drives proliferation.
what is the cancer associated with Myc transcription factor?
a translocation can lead to Burkitt’s lymphoma
what is the cancer associated with ha-ras and ki-ras g proteins?
a point mutation can lead to bladder and colon&lung cancer respectively
what are tumour suppressor genes (TSGs)?
encode proteins whose function is to regulate cellular proliferation and maintain cell integrity
– e.g. pRb.
how many copies of each TSG is present in cells? how many mutations are required to drive cancer?
Each cell has 2 copies of each TSG
mutation/deletion of 1 copy is (usually) insufficient to promote cancer
mutation or loss of BOTH copies means a loss of control.
what are common features of susceptibility to cancers due to TSG mutations?
- Family history
- Early age of onset
- Bilateral tumours in paired organs (seen with non-sporadic retinablastomas for example)
- Synchronous/successive tumours
- Different organ tumours in the same individual
- Mutation inherited through germline
what hypothesis describes the activation of cancer via TSGs?
Knudson’s 2 hit hypothesis
what is the difference between sporadic and inherited cancers due to TSGs?
sporadic–> 2 acquired mutations of TSGs (rare)
inherited –> 1 acquired mutation and 1 inherited mutation (more common)
what causes retinoblastoma?
Malignant cells of developing retinal ganglionic cells.
o Mutation of RB1 (retinoblastoma) TSG on Chr 13q14.
o RB1 encodes a nuclear regulation protein:retinoblastoma protein
- requires two mutated copies
treatment is to remove the eye
