Oncogenes and Tumour Suppressor Genes Flashcards
In which tissues are carcinoma found?
Epithelial
In which tissues are sarcomas found?
Muscle, blood vessels, bone, fibroblasts
In which tissues are leukaemia/lymphomas found?
Circulating cells of blood and lymph systems.
What is a benign tumour?
A tumour that does not invade surrounding tissue or spread to other organs.
What is a malignant tumour?
A tumour that invades and destroys adjacent normal tissue. It can spread to distant organs via the circulatory system.
Do most mutations cause cancer?
No, many are passenger mutations and not cancer causing.
What are the clonal origins of cancer?
Monoclonal - usually arises from one cell.
If cancer comes from mutation on X chromosome, for women cells can be identified as cancerous or not due to X-inactivation.
What kind of in vivo assays can be done?
Tumour formation in animals:
Transgenic and knockout strains
Application of cancer causing agents.
Give four of the main risk factors for cancer.
Smoking
Diet
Viruses
Family history
What is a protooncogene?
A gene that has a normal role and function, but the potential to do bad (cause cancer) if mutated.
What does CDK stand for?
Cyclin dependent kinases.
What is the restriction point?
Cells receive signals from outside telling it to proliferate. It will stop if signals stop, up until restriction point.
When would anaphase be blocked?
During mitosis - if chromatids are not properly assembled on mitotic spindle.
When would entrance to M be blocked?
End of G2 - if DNA replication is not completed.
When would entrance to S be blocked?
End of G1 - if genome is damaged.
What would be halted in the middle of S phase if the genome is damaged?
DNA replication.
Name 3 oncogenes.
ras
myc
bcl-2
Name two tumour suppressor genes.
p53
Rb
How many genes are in the Ras superfamily?
Nearly 50
What percentage of pancreatic carcinomas have activated ras?
95%
What percentage of human tumours have activated ras?
10-15%
Which type of ras is activated in lung carcinomas?
Kras
Which type of ras is activated in melanomas?
Nras
Which type of ras is activated in DMBA induced skin carcinomas?
Hras
With relation to GDP and GTP, what are activated and inactivated ras associated with?
Activated ras - GTP
Inactivated ras - GDP
Which signalling pathway is hyperactivated in most human cancers?
Ras-Raf-MEK-ERK
List some of the cellular processes controlled by ERK.
Proliferation Cell cycle Differentiation Transformation Survival Cytoskeleton Adhesion Matility etc.
What does RKIP disrupt?
The interaction between Raf and MEK.
What is Ras activated by?
Inactive Ras binds to GDP.
Activation occurs when a GEF exchanges GDP for GTP.
This causes a change of conformation that enables interaction with effector proteins, such as Ref, Pl-3 kinase etc.
De-activation is caused by hydrolysis of GTP.
What happens in oncogenic forms of Ras, with regard to GTP?
Oncogenic mutations lock Ras in the activated GTP bound form.
How does Ras activate Raf kinases?
The regulatory domain of Raf-1 restrains teh catalytic activity of the kinase domain. In the inactive state Raf-1 is found in the cytosol. The regulatory domain binds to Ras/GTP with high affinity, resulting in the translocation of Raf-1 to the plasma membrane where Ras is localised. This is the final step in Raf-1 activation. Activated Raf-1 phosphorylates and activates its substrate MEK.
How many genes are in the myc family?
At least 7 closely related genes with 3 exons.
What is the function of myc?
Nuclear transcription factor
Helix-loop-helix/leucine zipper proteins with DNA specific binding.
Bind DNA as Myc:Max dimers
High level expression accelerates cell growth, transactivates cyclins A and E and cdc25
Down regulation correlated with cell differentiation
Immortalises primary fibroblasts and co-operates with Ras to transform fibroblasts in culture
co-operates with Pim-1 and Bcl-2 in transgenic mice to accelerate lymphoma onset.
How was the bcl-2 gene first discovered?
As a translocation breakpoint, juxtaposing a portion of chromosome 18 to the IgH locus (chromosome 14) in human follicular lymphoma.
What does overexpression of bcl-2 promote?
Extended survival of some haematopoietic cell lines and blocks c-myc induced apoptosis.
What effect does apoptosis by members of the bcl-2 family have on mitochondria?
Leads to opening of channels in the mitochondrial membrane, releasing a ‘death cocktail’.
What’s caspase?
Cysteine aspartyl-specific proteases.
A cascade of proteases leads to death of the cell.
What happens to Rb throughout the cell cycle?
It is increasingly phosphorylated.
What is the consequence of phosphorylation of Rb in the cell cycle?
It releases E2F to activate transcription of the genes required for the next cell cycle stage. Transactivation of cyclin E provides a positive feedback loop.
E-CDK2 will then phosphorylate other ts proteins (like p27) which leads to their degradation, releasing more active E-CDK2 complexes.
What are the two major classes of tumour suppressor gene?
- Genes that maintain stability and integrity of the genomee: p53, excision repair genes (XP), mismatch repair genes (HNPCC) etc.
- Lineage growth control: RB, APC, BRCA1 etc.
What is Li-Fraumeni syndrome?
Families have a high incidence of tumours.
Risk of cancer 50% by age 30, 90% by age 50.
Due to germ line mutations in p53.
Describe the retroviral genome.
Approximately 8.5kb encoding gag, pol and env.
Carry reverse transcriptase, to reverse transcribe RNA into DNA.
What is the retroviral life cycle?
Invasion of host cell RNA to DNA dsDNA copy of the viral genome Circularised viral genome Viral genome integrated into host DNA provirus Viral mRNA Viral proteins Viral assembly Budding from cell membrane
How can retroviruses cause oncogenesis?
Some retroviruses carry additional viral genes which can act as oncogenes, eg. human T-cell leukaemia virus.
Retroviruses inducing long latency tumours, follow the standard viral life cycle, but on rare occasions may integrate near to an oncogene, which can lead to a tumour.
Acutely transforming retrovirus have gained new genetic information that was not present in the ancestral, non transforming virus.
What is the consequence of tumour antigens binding RB and sequestering it?
E2F is free, cell cycle is unchecked.
