Oncogenes & TSGs Flashcards
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.
Why are cycle checkpoints so important?
Ensure genetic fidelity
• specific proteins accumulate/are destroyed during the cycle (e.g. cyclins, Cdks, CdksI, etc.)
• permanent activation of a cyclin can drive a cell through a checkpoint (checkpoints marked)
Why are proto-oncogenes important?
Essential proteins involved in maintenance of
• cell growth
• division
• differentiation
What causes the formation of a oncogene?
Mutations = proto-oncogene –> oncogene
• whose protein product does NOT respond to control influences
Oncogenes can be aberrantly expressed, over-expressed or aberrantly active
• e.g. MYC, RAS, ERB
Proto-oncogenes can be converted to an oncogene by A SINGLE MUTATION
What are the ways that oncogenes can be activated?
The normal proto-oncogene can be activated in 4 ways:
- Mutation in the coding sequence
• point mutation or deletion - 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 - Chromosomal translocation
• Chimeric genes - Insertional mutagenesis
• 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
Explain the oncogene activation using the example of Philadelphia chromosome
This is an example of INSERTIONAL MUTAGENESIS
• the product created is a fusion protein of Bcr-Abl that encodes a tyrosine kinase receptor that does NOT SWITCH OFF and thus drives uncontrolled proliferation – CML
Translocation between Chr 9 and 22
Which type of proteins are critical proto-oncogenes and give examples
SIGNAL TRANSDUCTION PROTEINS are proto-oncogenes
Examples:
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.
Explain how RAS mutated in cancer
Upon binding GTP, RAS becomes active
• it’s the dephosphorylation of GTP –> GDP that switches RAS OFF
The binding of GTP allows RAS to bind RAF
• this passes the signal to RAF, delivering the signal further to MEK and ERK
• the dephosphorylation of GTP –> GDP then UNBINDS RAF from RAS
Mutant RAS fails to dephosphorylate GTP and remains active and bound to RAF and drives proliferation.
Oncogenes and Human Tumours - the table?
Onenote!!!
NEED TO KNOW!
Define TSGs
TSGs encode proteins whose function is to:
• regulate cellular proliferation
and
• maintain cell integrity
E.g. pRb
How do TSGs start to have cancerous effects?
Each cell has TWO copies of each TSG
• mutation/deletion of ONE copy is (usually) insufficient to promote cancer
• mutation or loss of BOTH copies means a loss of control
What are the features of cancer due to TSGs
o Family history
o Early age of onset
o Bilateral tumours in paired organs
o Synchronous/successive tumours
o Different organ tumours in the same individual
o Mutation inherited through germline
Explain how TSGs contribute to conditions such as Retinoblastoma
Malignant cells of developing retinal ganglionic cells
• Mutation of RB1 TSG on Chr 13q14
• RB1 encodes a nuclear regulation protein
A sporadic disease usually involving one eye. The hereditary versions can be
• uni/bilateral OR multifocal (multiple tumours)
Treatment is to remove the eye.
What are the different functional classes of TSGs?
- Regulate cell proliferation.
- Maintain cellular integrity.
- Regulate cell growth.
- Regulate cell cycle.
- Nuclear transcription factors.
- DNA repair proteins.
- Cell adhesion molecules.
- Cell death regulators.
Difference between TSGs and oncogenes?
TSGs SUPPRESS the neoplastic phenotype of a cell
VS
Oncogenes that ENABLE the neoplastic phenotype
TSG mutation examples?
Onenote!!
NEED TO KNOW!!
Explain the p53 and its importance
P53 may be a TSG BUT mutation of a SINGLE copy is enough to cause dysregulation of activity and cancer
• mutants of p53 act in a dominant matter
MDM2 keeps p53 in an inactive state and then when the cell comes under stress, p53 dissociates from MDM2 and becomes active by forming a p53 tetramer which then has cellular effects
What can APC TSG cause?
APC TSG deletion –> Familial adenomatous polyposis coli
Explain what a mutation in the APC TSG can lead to and how
A deletion in 5q21 –> loss of APC TSG
• APC is involved in cell adhesion & signalling and sufferers of APC loss develop multiple benign adenomatous polyps of the colon
• 90% risk of colorectal carcinoma
APC participates in the WNT signalling pathway.
• APC helps control activity of B-catenin and thereby prevents uncontrolled cell growth
• Mutation of APC is a frequent event in any colon cancer
3 ways Cancer can be triggered?
Oncogene + TSG
Proto-oncogene + defective TSG
Oncogene + defective TSG
Cnacer is achieved by multiple mutations such as in colo-rectal cancer - define which mutations
Apc - hyperproliferation
K-ras - adenoma
p53 - carcinoma
Metastasis
Features of Oncogenes
- Gene active in tumour
- Specific translocations/point mutations
- Mutations rarely hereditary
- Dominant at cell level
- Broad tissue specifity
- Leukaemia & lymphoma
Features of TSGs
- Gene inactive in tumour
- Deletions or mutations
- Mutations can be inherited
- Recessive at cell level
- Considerable tumour specificity
- Solid tumours
Which one of the following statements is NOT correct?
a. Mutation can convert a protooncogene to an oncogene
b. Gene amplification of a protooncogene can be oncogenic
c. Chromosome translocation can lead to inappropriate expression of a protooncogene and to an oncogenic effect.
d. A protooncogene can be activated to an oncogene by insertional mutagenesis
e. Protooncogenes are not expressed in normal cells.
C
The protein products of tumour suppressor genes are NOT involved with:
a. Regulation of cellular proliferation.
b. Metabolism of drugs
c. Regulation of cell cycle
d. Repair of DNA damage
e. Control of transcription
B
