Week 2: Oncogenes Flashcards
What are oncogenes?
Oncogenes are genes that produce products or cause the increased likelihood + drive to normal survival, growth + division. In cancer they are constantly active
Before the discovery of oncogenes
- We used to heavily believe that cancers were primarily caused by viruses
- Now we know that there are in fact tumour-causing genes in viral pathogens
- Rous believed that there was a transmissible agent to causing cancer
- Although this research for tumour-causing viruses didn’t amount to much, it was still invaluable information to scientists
- We found through RNA tumour viruses, that the virus would -reverse transcribe its DNA into the host DNA + chromosome
Rous’ experiment
1) Remove sarcoma from chicken, break it up into smaller chunks of tissue
2) Grind the sarcoma chunks with the sand
3) Pass the filtrate through a fine-pore filter
4) Filtrate is injected into new healthy chicken
5) Observe sarcoma growth in new chicken
- The experiment shwoed that the cells infected by Rous-Sarcoma Virus would be deformed + transformed
Properties of transformed cells
- Altered morphology
- Loss of contact inhibition
- Ability to grow without attachment to solid substrate
- Reduced requirement for mitogeninc growth factors
- Inability to halt proliferation in response to deprivation of growth factors
- Increased glucose transport
- Will form tumours when injected into another cell/host
The first connection betwen oncogenes + the function of normal cellular genes involved in the control of cell proliferation
- This connneciton first came from the sequencing of 2 viral oncogenes: V-sis + V-erbB in the early 80s
- V-= Oncogene
V-sis
- Shown to be a mutated but closely related product to the B-chain of platelet-derived growth factor
- Only works if the cell possesses PDGF receptor to make it cancerous
- Stimulates autocrine growth
V-erbB
- Shown to be a highly truncated + point-mutated version of the Epidermal Growth Factor (EGF) receptor
- EGF receptor is a member of receptor tyrosine kinase family
Activation by insertional mutagenesis
After integration of a virus into the host DNA, the expression of adjacent hos tgenes brought under the control of the powerful regulatory elements of the virus, which can lead to inappropriate/overexpression
Myc gene is very susceptible to viral insertional mutagenesis
- When the viral genome is inserted into the human DNA, myc expression is driven
- myc is only one example of cellular genes found to be activated by insertional mutagenesis
- Too much myc protein can cause cell cycle arrest + apoptosis
Ras gene
- A gene involved in driving cell proliferation + can regulate myc expression
- Identified as an oncogene by trasnfection of DNA
- Mutation hotspots in Ras are aa positions:
+ 12
+ 13
+ 59
+ 61 - aa 12 mutation affects nucleotide binding by reducing affinity
- aa 13,59, 61 mutations affects GTP hydrolysis mechanisms
- One of the most common mutations seen in cancer
Activating Ras mutations
- Activating Ras mutants act by increasing the time spent in active conformation either by:
+ Increasing rate of nucelotide exchange
+ Affecting the activation of the GTPase activity required to return Ras to the inactive state
