Edmead L2 - Proto-oncogenes to Oncogenes Flashcards
Oncogenes are genes that result in a _____.
The mutation happens at DNA level so when transcribed the protein either has:
1) Altered to ______ ______.
2) Been ______ __ ______ ______.
Altered to increase activity
Produced in higher quantities
Normal function of proto-oncogenes is to _____ ___ ____.
____ __ _____ mutations in proto-oncogenes activates them to become oncogenic.
They then encode proteins that can _______ cells.
Basically they are the normal cellular counterpart of a mutated gene that can cause tumours.
Control cell growth
Gain of function mutations
Transform
What are the three different types of mutation that can lead to oncogene formation?
1) Point mutation
2) Gene amplification
3) Chromosomal translocation
What is being described?
- DNA transversion and/or transition occurs
- Change in nucleotide from G to C changes codon and AA hence protein structure and function is altered
- OR a change in purine for pyrimidine occurs
- This results in a gain of function so the protein can become constitutively active and promotes growth all the time.
Give an example of a protein.
Point mutations
Point mutations in the gene encoding RAS can result in RAS becoming constitutively active
Cells are constantly signalled to grow and proliferate and a tumour can result
What is being described?
- If when a cell proliferates, it copies DNA but slips and copies the same length of DNA again this can lead to increased numbers of the gene
- This then leads to increased amount of the protein being produced (over expression of the gene occurs)
- This can lead to increased growth and mass formation
N.B it is a wild type copy just more of the protein around
Give an example of a protein
Gene amplification
What is being described?
- Change in the chromosome where part breaks off and moves to another chromosome
- Genes are regulated by promoter regions - if the gene breaks off and moves from an area of low transcription to high transcription then more protein produced
Give an example of a protein
Chromosomal translocation
E.g. BCL2 locus translocates to area next to heavy chain enhancer which is very active in B cells. BCL2 is anti-apoptotic and expressed in higher levels after translocation leading to B cell lymphoma (apoptosis reduced so more cell survival)
Src is a ____ _____ (phosphorylates proteins) involved in growth and survival pathways
Tyrosine kinase
c-Src is a ______ whereas V-Src is a ______
c-Src is a proto-oncogene whereas v-Src is an oncogene (altered form transduced by retrovirus)
Describe INACTIVE and ACTIVE Src
Inactive Src: SH2 domain is bound to phosphorylated Tyrosine 527 residue meaning it is in a ‘closed’ or inactive confirmation
Inactive Src becomes active when phosphateases that dephosphorylate it or when phosphorylated receptors e.g. EGFR interact with the SH2 domain disrupting the -ve regulatory intramolecular conformation
Active Src: The tyrosine 527 is dephosphorylated thus it is unable to bind to the SH2 domain resulting in an ‘open’, active conformation this can then phosphorylate target proteins including FAK and transcription factors
List a way in which Src can become constitutively active
Mutational activation e.g. mutation or deletion of tyrosine 527
- In sarcomas, the Rous sarcoma virus integrates it’s genetic material into chicken genome so that the DNA is next to the Src gene
- This genetic material is then excised to make a new viral particle and it takes some of the Src gene with it BUT doesn’t include the C terminal tyrosine (527)
- The virus can then integrate it’s genetic material into another chickens host DNA and the Src protein is then make w/o the C terminal tyrosine residue 527
- The infected chickens acquire the version of Src missing the regulatory domain so the Src becomes constitutively active as it cannot fold up into the close conformation
- This leads to the Src being able to phosphorylate target proteins such as FAK and transcription factors which can then lead to tumour growth
- HER2 - _____ AA is part of the transmembrane region (_____ so sits in the membrane)
- EGF binds and dimerises 2 subunits of the receptor and causes activation of intracellular signalling domain (_____ domain)
- This then uses ATP to phosphorylate downstream targets
Valine
Hydrophobic
Kinase domain
- _____ can get mutated through _____ mutation to become glutamine
- Glutamine is a _____ AA so not favourable to sit in lipid membrane so it tries to minimise the disruption but this causes _______ of the 2 receptor chains
- This activates intracellular domains so receptor signals w/o ligands
- It then becomes ______ _____
- This form is referred to as the ___ _____ (mutated form of the HER2 receptor) - point mutation
- This is a point mutation and is seen in ______ cancer
What can you treat this with?
Valine Point Charged Dimerisation Constitutively active Lung
You can treat this with small molecule inhibitors e.g. Iressa/Tarceva which block the kinase domain, preventing downstream signalling
The HER2 receptor is susceptible to amplification where there is no change in ____ and it is still regulated by a ligand. There’s just more receptors, so more chance of a ligand interacting with receptor and causes more growth. This can lead to _____ cancer and is due to ______ _______ and cells are more sensitive to growth factors.
Valine
Breast
Template slippage
HER2 is amplified in around __% of breast cancers and HER2 over expression leads to cell ______ and induction of breast cancer.
30
Induction
In cases where HER2 is over expressed e.g. ____ cancer. mAbs e.g. _____ can be used to block _____ _____. This prevents _______ of the receptor. It doesn’t work in cancers where HER2 is constitutively active as they are ligand independent (so doesn’t work in ____ cancer).
Breast Herceptin Ligand binding Dimerisation Lung
